Substituted imidazoles

ABSTRACT

This invention relates to a range of alpha substituted 2-benzyl substituted imidazole compounds and pharmaceutically acceptable salts and solvates thereof, to compositions comprising such compounds, processes for their synthesis and their use as parasiticides.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/619,735 filed Jan. 4, 2007, now pending, which claims the priority toprovisional application Ser. No. 60/760,765 filed Jan. 19, 2006.

This invention relates to imidazoles having parasiticidal properties.The compounds of interest are substituted imidazoles and, moreparticularly, the invention relates to alpha substituted 2-benzylimidazoles.

There is a need for improved antiparasitic agents for use with mammals,including humans and animals, and in particular there is a need forimproved insecticides and acaricides. Furthermore there is a need forimproved topical products with convenient administration and whichcontain one or more of such antiparasitic agents which can be used toeffectively treat ectoparasites, such as insects and acarids, andparticularly aracids such as mites and ticks. Such products would beparticularly useful for the treatment of companion animals, such ascats, dogs and horses, and livestock, such as cattle. There is equally aneed for agents to control parasitic infestations in animal hosts otherthan mammals, including insects such as bees, which are susceptible toparasites such as varroa mites.

The compounds currently available for insecticidal and acaricidaltreatment of companion animals and livestock do not always demonstrategood activity, good speed of action, or a long duration of action. Mosttreatments contain hazardous chemicals that can have seriousconsequences when either used too often or when used in excess ofrecommended quantities. Many products have toxic side effects and someare lethal to cats when accidentally ingested. They are not alwayssuitable for use as a topical or spot-on formulation and some topicaland spot-on formulations are disadvantaged by common side effects inanimals and owners. Persons applying these insecticidal and acaricidalagents are advised to limit their exposure to the chemicals by wearinggloves and avoiding inhalation of the chemical vapours. Pet collars andtags have been utilised to overcome some problems, but these aresusceptible to chewing and therefore are disadvantageous since thecompound may be accidentally orally ingested. Thus, treatments currentlyachieve varying degrees of success depending on a variety of factorsincluding toxicity and the method of administration. In some casestoxicity may be attributed to their non-selective activity at variousreceptors. In addition it has recently been shown that some currentagents are becoming ineffective as the parasites develop resistance.

The present invention overcomes one or more of the various disadvantagesof, or improves upon, the properties of existing compounds. Inparticular the present invention develops some new alpha substituted2-benzyl imidazoles which demonstrate such properties.

Heterocyclic derivatives have been disclosed in the prior art as havinginsecticidal and acaricidal activity against agricultural pests, forexample International patent application publication no. WO 03/092374.

Generic disclosures also exist in the prior art of heterocyclicderivatives which optionally encompass alpha substituted 2-benzylimidazoles. For example, international patent application publicationno. WO 2005/007188 describes a generic structure, which optionallyencompasses alpha substituted 2-benzyl imidazoles for the inhibition ofthe hatching of an ectoparasite egg; international patent applicationpublication no. WO 2004/103959 describes a generic structure whichoptionally encompasses alpha substituted 2-benzyl imidazoles for use asantibacterial agents; international patent applications publication nosWO 01/00586 and WO 99/28300 both describe a generic structure whichoptionally encompasses alpha substituted 2-benzyl imidazoles anddiscloses their adrenergic activity; and U.S. Pat. No. 6,103,733describes a generic structure which optionally encompasses alphasubstituted 2-benzyl imidazoles for increasing blood serum and HDLcholesterol levels. However, none of this prior art exemplifies anyalpha substituted 2-benzyl imidazoles, nor does the prior art indicatethat such compounds would be useful against a spectrum of parasitesrelevant to companion animals and livestock or against the range ofectoparasite lifecycle stages.

Thus, it is an aim of the present invention to overcome one or more ofthe various disadvantages of, or improve on the properties of, knowncompounds. In particular it is an aim of the invention to develop somenew alpha substituted 2-benzyl substituted imidazoles. It is a furtheraim that such new compounds have the same or improved activity whencompared to the prior art compounds against parasites. It is another aimof the present invention to develop compounds which have a similar ordecreased toxicity profile when compared to the prior art compounds. Itis yet another aim to develop compounds which demonstrate selectivityfor the octopaminergic receptor, a known invertebrate neurotransmitter,over the ubiquitous animal adrenergic receptor. Furthermore, it is anaim of the invention to reduce the exposure of both humans and animalsto the treatment by developing compounds which can be dosed as a lowvolume spot-on or topical application. The compounds of the presentinvention have especially good ability to control arthropods as shown bythe results of tests demonstrating their potency and efficacy. Inparticular, the compounds of the present invention are active againstticks and they are able to prevent ticks from attaching to, and feedingfrom, the host animal. It is yet another aim of the present invention toprovide compounds which have good speed of action when compared to thoseof the prior art and hence an improved efficacy against the transmissionof tick borne diseases.

It is also desirable that the compounds of the present invention shouldhave one or more of the same or improved duration of action, an improvedpharmacokinetic profile, improved safety, improved persistence, improvedsolubility or other improved physicochemical and formulation propertiessuch as good spreading after topical application compared to those ofthe prior art.

Thus, according to the present invention, there is provided a compoundof formula (I):

wherein:

-   R¹, R², R³, R⁴, R⁵ are independently selected from the group    consisting of hydrogen, cyano, nitro, halo, hydroxy, C₁₋₄ alkyl    optionally substituted by one or more hydroxy groups, C₃₋₆    cycloalkyl optionally substituted by one or more C₁₋₄ alkyl or halo    groups, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, amino,    NR^(x)R^(y), and S(O)_(n)R¹⁰;-   R⁶ is selected from the group consisting of hydrogen,    —C₀₋₂alkyleneR⁷, —C₁₋₂alkyleneOR⁷, —C₀₋₂alkyleneC(O)R⁷,    —C₁₋₂alkyleneOC(O)R⁷, —C₁₋₂alkyleneOC(O)OR⁷, —C₀₋₂alkyleneC(O)OR⁷,    —C₁₋₂alkyleneN(H)C(O)R⁷, —C₁₋₂alkyleneN(R⁷)C(O)R⁷,    —C₀₋₂alkyleneC(O)NHR⁷, —C₀₋₂alkyleneC(O)NR¹⁵R¹⁶,    —C₁₋₂alkyleneNHC(O)NR¹⁵R¹⁶, —C₁₋₂alkyleneNR⁷C(O)NR¹⁵R¹⁶,    —C₁₋₂alkyleneOC(O)NHR⁷, —C₁₋₂alkyleneOC(O)NR¹⁵R¹⁶,    —C₀₋₂alkyleneCH═N(R⁷), —C₁₋₂alkyleneP(═O)(NR¹⁵R¹⁶)(NR¹⁵R¹⁶),    —C₀₋₂alkyleneSi(R⁷)₃, and —C₀₋₂alkyleneS(O)_(n)R¹⁰;-   where the C₀₋₂alkylene or C₁₋₂alkylene of R⁶ may, where chemically    possible, optionally be substituted by one or more substituents    selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,    C₁₋₄ alkylene(C₃₋₆ cycloalkyl), C₀₋₆ alkylenephenyl, which    C₀₋₂alkylene or C₁₋₂alkylene substituent may in turn be optionally    further substituted, where chemically possible, by one or more    substituents selected from the group consisting of hydrogen, cyano,    nitro, halo, formyl, oxo, hydroxy, C(O)OH, C₁₋₄ alkyl, C₁₋₄    alkyleneC₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkyleneC₁₋₄ alkyoxy,    —C(O)OC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, amino, C₁₋₄    alkylamino, C₁₋₄ dialkylamino, and S(O)_(n)R¹⁰;-   where each R⁷, R¹⁵ and R¹⁶, where chemically possible, is    independently selected from the group consisting of hydrogen, C₁₋₈    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₁₋₄    alkylene(C₃₋₆ cycloalkyl), C₁₋₄ alkyleneC₁₋₄ alkoxy, C₁₋₆ haloalkyl,    C₀₋₆ alkylenephenyl, C₀₋₆ alkylenenaphthyl, C₀₋₆    alkylene(tetrahydronaphthyl), and C₀₋₂ alkylene(Het), where Het is    selected from oxetanyl, tetrahydropyranyl, piperidinyl, morpholinyl,    furyl, pyridyl, benzofuranyl, benzothiazolyl, indolyl,    2,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, indolyl and    1,5-naphthyridinyl;-   or R¹⁵ and R¹⁶ together with the nitrogen to which they are attached    may form a three to seven-membered saturated or unsaturated    heterocyclic ring optionally containing one or more further N, O or    S atoms or SO₂ groups;-   where each of the above R⁷, R¹⁵ or R¹⁶ groups may independently    include one or more optional substituents where chemically possible    selected from hydrogen, cyano, nitro, halo, formyl, oxo, hydroxy,    C(O)OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl,    C₁₋₄ alkyleneC₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkyleneC₁₋₄    alkyoxy, C₁₋₄ alkoxyC₁₋₄ alkoxy, C₁₋₄ alkanoyl, —C(O)OC₁₋₄ alkyl,    C₁₋₄ haloalkyl, C₃₋₆ halocycloalkyl, C₁₋₄ haloalkoxy, C₁₋₄    haloalkanoyl, —C(O)OC₁₋₄ haloalkyl, phenyl, 4-halophenyl,    4-alkoxyphenyl, 2-cyanophenyl, phenoxy, 4-halophenoxy, benzyloxy,    4-halobenzyloxy, benzoyl, pyrazolyl, triazolyl,    2-halo-4-pyrimidinyl, 2-phenylethyl, amino, C₁₋₄ alkylamino, C₁₋₄    dialkylamino, C(O)N(C₁₋₄ alkyl)₂, N(C₁₋₄ alkylene)C(O)(C₁₋₄ alkyl)    and S(O)_(n)R¹⁰;-   R⁸ and R⁹ are independently selected from the group consisting of    hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy    and C₀₋₄ alkylenephenyl but with the proviso that R⁸ and R⁹ are not    both hydrogen;-   where each of R⁸ and R⁹ may independently include one or more    optional substituents where chemically possible selected from    hydrogen, cyano, halo, hydroxy, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄    alkoxy, —C(O)OC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and    S(O)_(n)R¹⁰;-   or R⁸ and R⁹ together with the carbon to which they are attached may    form a three to six membered carbocyclic, saturated ring, which ring    is optionally substituted with one or more substituents selected    from the group consisting of halo, C₁₋₂ alkyl, C₁₋₂ alkoxy, C₁₋₂    haloalkyl, C₁₋₂ haloalkoxy;-   R¹¹ and R¹² are independently selected from the group consisting of    hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and    C₁₋₄ haloalkoxy;-   where R^(x) and R^(y) are independently selected from hydrogen, C₁₋₄    alkyl, C₁₋₄ haloalkyl, and S(O)_(n)R¹⁰;-   each n is independently 0, 1 or 2;-   and each R¹⁰ is independently hydrogen, hydroxy, C₁₋₄ alkyl, C₁₋₄    haloalkyl, 4-halophenyl, amino, C₁₋₆ alkyl amino and di C₁₋₆ alkyl    amino;    or a pharmaceutically acceptable salt or a prodrug thereof.

In particular, there is provided a compound of formula (I):

wherein:

-   R¹, R², R³, R⁴, R⁵ are independently selected from the group    consisting of hydrogen, cyano, nitro, halo, hydroxy, C₁₋₄ alkyl,    C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy,    amino, NR^(x)R^(y), and S(O)_(n)R¹⁰;-   R⁶ is selected from the group consisting of hydrogen,    —C₀₋₂alkyleneR⁷, —C₁₋₂alkyleneOR⁷, —C₀₋₂alkyleneC(O)R⁷,    —C₁₋₂alkyleneOC(O)R⁷, —C₁₋₂alkyleneOC(O)OR⁷, —C₀₋₂alkyleneC(O)OR⁷,    —C₁₋₂alkyleneN(H)C(O)R⁷, —C₁₋₂alkyleneN(R⁷)C(O)R⁷,    —C₀₋₂alkyleneC(O)NHR⁷, —C₀₋₂alkyleneC(O)NR¹⁵R¹⁶,    —C₁₋₂alkyleneNHC(O)NR¹⁵R¹⁶, —C₁₋₂alkyleneNR⁷C(O)NR¹⁵R¹⁶,    —C₁₋₂alkyleneOC(O)NHR⁷, —C₁₋₂alkyleneOC(O)NR¹⁵R¹⁶,    —C₀₋₂alkyleneCH═N(R⁷), —C₁₋₂alkyleneP(═O)(NR¹⁵R¹⁶)(NR¹⁵R¹⁶),    —C₀₋₂alkyleneSi(R⁷)₃ and —C₀₋₂alkyleneS(O)_(n)R¹⁰;-   where the C₀₋₂alkylene or C₁₋₂alkylene of R⁶ may, where chemically    possible, optionally be substituted by one or more substituents    selected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,    C₁₋₄ alkylene(C₃₋₆ cycloalkyl), C₀₋₆ alkylenephenyl, which    C₀₋₂alkylene or C₁₋₂alkylene substituent may in turn be optionally    further substituted, where chemically possible, by one or more    substituents selected from the group consisting of hydrogen, cyano,    nitro, halo, formyl, oxo, hydroxy, C(O)OH, C₁₋₄ alkyl, C₁₋₄    alkyleneC₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkyleneC₁₋₄ alkyoxy,    —C(O)OC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, amino, C₁₋₄    alkylamino, C₁₋₄ dialkylamino, and S(O)_(n)R¹⁰;-   where each R⁷, R¹⁵ and R¹⁶, where chemically possible, is    independently selected from the group consisting of hydrogen, C₁₋₈    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₁₋₄    alkylene(C₃₋₆ cycloalkyl), C₁₋₄ alkyleneC₁₋₄ alkoxy, C₁₋₆ haloalkyl,    C₀₋₆ alkylenephenyl;-   or R¹⁵ and R¹⁶ together with the nitrogen to which they are attached    may form a three to seven-membered saturated or unsaturated    heterocyclic ring optionally containing one or more further N, O or    S atoms;-   where each of the above R⁷, R¹⁵ or R¹⁶ groups may independently    include one or more optional substituents where chemically possible    selected from hydrogen, cyano, nitro, halo, formyl, oxo, hydroxy,    C(O)OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl,    C₁₋₄ alkyleneC₃₋₆ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkyleneC₁₋₄    alkyoxy, C₁₋₄ alkanoyl, —C(O)OC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₆    halocycloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkanoyl, —C(O)OC₁₋₄    haloalkyl, phenyl, 4-halophenyl, 4-alkoxyphenyl, amino, C₁₋₄    alkylamino, C₁₋₄ dialkylamino, C(O)N(C₁₋₄ alkyl)₂, N(C₁₋₄    alkylene)C(O)(C₁₋₄ alkyl) and S(O)_(n)R¹⁰;-   R⁸ and R⁹ are independently selected from the group consisting of    hydrogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy    and C₀₋₄ alkylenephenyl but with the proviso that R⁸ and R⁹ are not    both hydrogen;-   where each of R⁸ and R⁹ may independently include one or more    optional substituents where chemically possible selected from    hydrogen, cyano, halo, hydroxy, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄    alkoxy, —C(O)OC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and    S(O)_(n)R¹⁰;-   or R⁸ and R⁹ together with the carbon to which they are attached may    form a three to six membered carbocyclic, saturated ring, which ring    is optionally substituted with one or more substituents selected    from the group consisting of halo, C₁₋₂ alkyl, C₁₋₂ alkoxy, C₁₋₂    haloalkyl, C₁₋₂ haloalkoxy;-   R¹¹ and R¹² are independently selected from the group consisting of    hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and    C₁₋₄ haloalkoxy;-   where R^(x) and R^(y) are independently selected from hydrogen, C₁₋₄    alkyl, C₁₋₄ haloalkyl, and S(O)_(n)R¹⁰;-   each n is independently 0, 1 or 2;-   and each R¹⁰ is independently hydrogen, hydroxy, C₁₋₄ alkyl, C₁₋₄    haloalkyl, amino, C₁₋₆ alkyl amino and di C₁₋₆ alkyl amino;    or a pharmaceutically acceptable salt or a prodrug thereof.

In the definition of R¹, R², R³, R⁴ and R⁵, “C₁₋₄ alkyl optionallysubstituted by one or more hydroxy groups” means an alkyl group withbetween one and four carbon atoms, which may be unsubstituted or may besubstituted at any available position with a hydroxy group. For reasonsof chemical stability, it is preferred that no carbon atom should besubstituted with more than one hydroxy group. Accordingly, alkyl groupswith up to four hydroxy substituents are foreseen. Preferred are alkylgroups with no more than two hydroxy substituents. Examples includehydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl and2,3-dihydroxypropyl.

In the definition of R¹, R², R³, R⁴ and R⁵, “C₃₋₆ cycloalkyl optionallysubstituted by one or more C₁₋₄ alkyl or halo groups” means a cycloalkylgroup with between three and six carbon atoms in the ring, which may beunsubstituted or may be substituted at any available position with analkyl group of between one and four carbon atoms or a halogen atom. Inthe case of alkyl substituents, it is preferred that not more than foursuch substituents be present, and more preferred that not more than twosuch substituents be present. Examples include 1-methylcyclopropyl,2,5-dimethylcyclopentyl and 4-tert-butylcyclohexyl. In the case of halosubstituents, any degree of substitution up to complete substitution isforeseen. In the case of cyclohexyl therefore, up to eleven halosubstituents may be present. While each halo group may be independentlyselected, it may be preferred to have all halo substituents the same.Preferably the halo is chloro or fluoro. Geminal disubstitution at anymethylene position may be preferred ver monosubstitution. Examplesinclude 2,2-dichlorocyclopropyl and perfluorocyclohexyl. Substitutionwith both alkyl and halo groups is also foreseen. An example is2,2-difluoro-1-methylcyclobutyl.

Preferably, each of R¹, R², R³, R⁴, R⁵ are independently selected fromhydrogen, halo eg chloro or fluoro, C₁₋₄ alkyl eg methyl or ethyl, C₃₋₄cycloalkyl eg cyclopropyl, C₁₋₄ alkoxy eg methoxy or ethoxy, C₁₋₄haloalkyl eg trifluoromethyl, trifluoroethyl, C₁₋₄ haloalkoxy egtrifluoromethoxy or trifluoroethoxy, and S(O)_(n)R¹⁰ where n is 0 andR¹⁰ is preferably selected from C₁₋₄ alkyl such as methyl or ethyl orC₁₋₄ haloalkyl such as trifluoromethyl or trifluoroethyl to form forexample trifluoromethylthio or trifluoroethylthio. More preferably eachof R¹, R², R³, R⁴, R⁵ are independently selected from hydrogen, halo egchloro, C₁₋₄ alkyl eg methyl or ethyl, C₁₋₄ alkoxy eg methoxy or ethoxy,and C₁₋₄ haloalkyl eg trifluoromethyl, trifluoroethyl. Most preferablyeach of R¹, R², R³, R⁴, R⁵ are independently selected from hydrogen, andC₁₋₄ alkyl eg methyl or ethyl.

Most preferably two of R¹, R², R³, R⁴, and R⁵ are independently selectedfrom C₁₋₄ alkyl eg methyl or ethyl, preferably methyl, and three of R¹,R², R³, R⁴, and R⁵ are H. Even more preferably R¹ and R² are selectedfrom C₁₋₄ alkyl eg methyl or ethyl, preferably methyl, and R³, R⁴ and R⁵are H.

Further suitable compounds include those where at least one of R¹, R²,R³, R⁴, and R⁵ is independently selected from C₁₋₄ haloalkyl egtrifluoromethyl, trifluoroethyl, preferably trifluoromethyl, with theothers of R¹, R², R³, R⁴, and R⁵ being H. Preferably R² is C₁₋₄haloalkyl eg trifluoromethyl, trifluoroethyl preferably trifluoroethyl,with the others of R¹, R³, R⁴, and R⁵ being H.

Other suitable compounds include those where at least one of R¹, R², R³,R⁴, and R⁵ is independently selected from C₁₋₄ alkoxy eg methoxy orethoxy preferably methoxy, with the others of R¹, R², R³, R⁴, and R⁵being H. Preferably R² and R³ are selected from C₁₋₄ alkoxy eg methoxyor ethoxy preferably methoxy, and R¹, R⁴ and R⁵ are H.

Other suitable compounds include those where at least one of R¹, R², R³,R⁴, and R⁵ is independently selected from halo eg chloro or fluoro, withthe others of R¹, R², R³, R⁴, and R⁵ being H.

Other suitable compounds include those where at least one of R¹, R², R³,R⁴, and R⁵ is independently selected from halo eg chloro or fluoro, andanother one of R¹, R², R³, R⁴, and R⁵ is independently selected fromC₁₋₄ alkyl eg methyl or ethyl, with the others of R¹, R², R³, R⁴, and R⁵being H.

Most preferred compounds are those where R¹ and R² are methyl and R³,R⁴, and R⁵ are hydrogen.

Preferably R⁶ is selected from the group consisting of hydrogen;—C₀₋₂alkyleneR⁷; —C₁₋₂alkyleneOR⁷; —C₁₋₂alkyleneOC(O)R⁷;—C₁₋₂alkyleneOC(O)OR⁷; —C₀₋₂alkyleneC(O)OR⁷; —C₁₋₂alkyleneOC(O)NHR⁷;—C₁₋₂alkyleneOC(O)NR¹⁵R¹⁶; and —C₀₋₂alkyleneS(O)_(n)R¹⁰. More preferablyR⁶ is selected from the group consisting of hydrogen; —C₀₋₂alkyleneR⁷;—C₁₋₂alkyleneOR⁷; —C₁₋₂alkyleneOC(O)R⁷; —C₁₋₂alkyleneOC(O)OR⁷; and—C₀₋₂alkyleneC(O)OR⁷. Even more preferably R⁶ is selected from the groupconsisting of hydrogen; —C₀₋₂alkyleneR⁷; —C₁₋₂alkyleneOC(O)R⁷ and—C₀₋₂alkyleneC(O)OR⁷. Most preferably R⁶ is hydrogen.

Preferably R⁷, R¹⁵ and R¹⁶ are, where chemically possible, independentlyselected from the group consisting of hydrogen; C₁₋₈ alkyl for examplemethyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl,n-pentyl, n-hexyl; C₃₋₈ cycloalkyl for example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl; C₁₋₄ alkylene(C₃₋₆ cycloalkyl) for examplecyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl,cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl;C₁₋₆ haloalkyl for example fluoromethyl, trifluoromethyl, chloromethyl,fluoroethyl, chloroethyl, trifluoroethyl and trifluoropropyl; and C₀₋₆alkylphenyl for example phenyl, phenylmethyl and phenylethyl. Morepreferably R⁷, R¹⁵ and R¹⁶ are, where chemically possible, independentlyselected from the group consisting of hydrogen; C₁₋₆ alkyl for examplemethyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, n-pentyl,n-hexyl; C₁₋₄ alkylene(C₃₋₆ cycloalkyl) for example cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl,cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl. Even morepreferably R⁷, R¹⁵ and R¹⁶ are, where chemically possible, independentlyselected from the group consisting of hydrogen and C₁₋₄ alkyl forexample methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl.

Further suitable compounds include those where R⁷, R¹⁵ and R¹⁶ are,where chemically possible, optionally substituted with one or moresubstituents selected from the group consisting of halo for examplefluoro or chloro, C₁₋₄ alkyl for example methyl or ethyl preferablymethyl, C₃₋₆ cycloalkyl, for example cyclopropyl, cyclobutyl orcyclopentyl preferably cyclopentyl, C₁₋₄ alkoxy for example methoxy orethoxy, C₁₋₄ haloalkyl for example fluoromethyl, chloromethyl,trifluoromethyl, fluoroethyl, chloroethyl or trifluoroethyl, preferablytrifluoroethyl or trifluoromethyl, and S(O)_(n)R¹⁰ for examplemethylsulphonyl or dimethyl amido sulphonyl. Examples of R⁷, R¹⁵ and R¹⁶groups which have then been so substituted include for example branchedalkyl groups such as 2-methylbutyl, 3-methylbutyl, substituted sulphonylgroups such as methylsulphonylmethyl, methylsulphonylethyl,dimethylamidosulphonylmethyl and dimethylamidosulphonylethyl andsubstituted phenyl groups such as 4-chlorophenyl, 4-nitrophenyl,4-fluorophenyl, 4-methoxyphenyl, 2,4-dichlorophenyl,4-chlorophenylmethyl, 4-nitrophenylmethyl, 4-fluorophenylmethyl,4-methoxyphenyl methyl, 2,4-dichlorophenylmethyl, 4-chlorophenylethyl,4-nitro phenyl ethyl, 4-fluorophenylethyl, 4-methoxyphenylethyl, and2,4-dichlorophenylethyl.

Suitably when R¹⁵ and R¹⁶ together with the nitrogen to which they areattached form a three to seven-membered saturated or unsaturatedheterocyclic ring optionally containing one or more further N, O or Satoms it is preferred that the ring is a five or six membered ring, issaturated and comprises one further heteroatom selected from N, O or S.Suitable examples of such rings include pyrrolidinyl, pyrazolidinyl,imidazolinyl, thiazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl,morpholinyl, or thiomorpholinyl. Preferred rings include pyrrolidinyl,thiazolidinyl, morpholinyl, or thiomorpholinyl. Such rings mayoptionally be further substituted with one or more groups, preferablyselected from the group consisting of oxo, C(O)OH, halo for examplefluoro or chloro, and C₁₋₄ alkyl for example methyl or ethyl preferablymethyl. For example any heterocyclic sulphur atoms may be optionallysubstituted with one or more oxo groups to form for example1,1-dioxothiazolidinyl or 1,1-dioxothiomorpholinyl substitutents.

Suitable compounds include those where, when the R⁶ group comprises aone carbon alkylene moiety, that said alkylene moiety is optionallysubstituted with one or two substituents. Further suitable compoundsalso include those where, when the R⁶ group comprises a two carbonalkylene moiety, that said alkylene moiety is optionally substitutedwith one, two, three or four substituents which may be independentlyorientated on either the alpha or beta carbon positions with respect tothe imidazole nitrogen to which the R⁶ substitutent is bound.

Suitably when the C₀₋₂alkylene or C₁₋₂alkylene of R⁶ is substituted withone or more substitutents it is preferred that such substituents areindependently selected from the group consisting of hydrogen; C₁₋₄ alkylfor example methyl or ethyl; C₃₋₆ cycloalkyl for example cyclopropyl;C₁₋₄ alkyleneC₃₋₆ cycloalkyl for example cyclopropylmethyl orcyclopropylethyl; C₁₋₄ alkoxy for example methoxy or ethoxy; C₁₋₄alkyleneC₁₋₄ alkyoxy for example methoxy methyl, methoxy ethyl, ethoxymethyl or ethoxy ethyl; C₁₋₄ haloalkyl for example fluoromethyl,trifluoromethyl, fluoroethyl or 1,1,1-trifluoroethyl; phenyl, benzyl and4-trifluoromethylbenzyl. More preferably such substituents areindependently chosen from the group consisting of hydrogen; C₁₋₄ alkylfor example methyl or ethyl; C₃₋₆ cycloalkyl for example cyclopropyl;C₁₋₄ alkyleneC₃₋₆ cycloalkyl for example cyclopropylmethyl orcyclopropylethyl; C₁₋₄ haloalkyl for example fluoromethyl,trifluoromethyl, fluoroethyl or 1,1,1-trifluoroethyl; and phenyl.

Suitable compounds include those where R⁶ is selected from the groupconsisting of —C₀₋₂alkyleneR⁷, preferably where R⁶ is CH₂R⁷, and whereR⁷ is selected from the group consisting of C₁₋₈ alkyl for examplemethyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl; C₃₋₈ cycloalkylfor example cyclopropyl, cyclobutyl, cyclopentyl; C₁₋₆ haloalkyl forexample trifluoromethyl, and trifluoroethyl; and C₀₋₆ alkylene-phenylfor example phenyl which is optionally substituted to form for example4-methoxy phenyl, 4-trifluoromethylphenyl. Further suitable compoundsalso include those where R⁶ is selected from the group consisting of—C₀₋₂alkyleneR⁷, preferably where R⁶ does not comprise an additionalalkylene moiety (ie is C₀alkyleneR⁷)⁷, and where R⁷ is selected from thegroup consisting of C₁₋₈ alkyl for example methyl, ethyl, n-propyl,isopropyl, butyl, tert-butyl, preferably methyl and ethyl; C₃₋₈cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl, preferablycyclopropyl; C₁₋₆ haloalkyl for example trifluoromethyl, andtrifluoroethyl; and C₀₋₆ alkylenephenyl for example phenyl which isoptionally substituted to form for example 4-methoxy phenyl,4-trifluoromethylphenyl.

A further group of suitable compounds include those where R⁶ is selectedfrom the group consisting of —C₁₋₂alkyleneOR⁷, preferably where R⁶ isCH₂OR⁷, and where R⁷ is selected from the group consisting of C₁₋₈ alkylfor example methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl.Examples of such so substituted R⁶ groups include methoxymethyl,ethoxymethyl, methoxyethyl, ethoxyethyl, propoxymethyl, propoxyethyl,isopropoxyethyl, butoxymethyl, sec-butoxyoxymethyl, isobutoxymethyl,tert-butoxymethyl, butoxyethyl, sec-butoxyoxyethyl, isobutoxyethyl,tert-butoxyethyl, pentyloxymethyl, pentyloxyethyl, hexyloxymethyl,hexyloxyethyl.

A still further group of suitable compounds include those where R⁶ isselected from the group consisting of —C₁₋₂alkyleneOC(O)R⁷, preferablywhere R⁶ is CH₂OC(O)R⁷, and where R⁷ is C₁₋₈ alkyl for example methyl,ethyl, n-propyl, isopropyl, butyl, tert-butyl, which R⁷ in turn may beoptionally further substituted. Examples of such so substituted R⁶groups include acetyloxymethyl, acetyloxyethyl, propionyloxymethyl,propionyloxyethyl, butyryloxymethyl, butyryloxyethyl,isobutyryloxymethyl, isobutyryloxyethyl, pentanoyl-oxymethyl,pentanoyloxyethyl, 2-methylbutyryloxymethyl, 2-methylbutyryloxyethyl,3-methylbutyryloxy-methyl, 3-methylbutyrylcarbonyloxy)ethyl,2,2-dimethylpropionyloxymethyl, 2,2-dimethyl propionyloxyethylhexanoyloxymethyl, hexanoyloxyethyl, heptanoyloxymethyl,heptanoyloxyethyl. Further suitable examples of compounds where R⁶ isselected from the group consisting of —C₁₋₂alkyleneOC(O)R⁷, preferablywhere R⁶ is CH₂OC(O)R⁷, also include those where R⁷ is C₁₋₄alkylene(C₃₋₆ cycloalkyl) for example cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl,cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, andcyclohexylethyl. Examples of such so substituted R⁶ groups includecyclopropylacetyloxymethyl, cyclopropylpropionyloxymethyl,cyclobutylacetyloxymethyl, cyclobutylpropionyloxymethyl,cyclopentylacetyloxymethyl, cyclopentylpropionyloxymethyl,cyclopentylbutyryloxymethyl, cyclohexylacetyloxymethyl, andcyclohexylpropionyloxymethyl, cyclopropylacetyloxyethyl,cyclopropylpropionyloxyethyl, cyclobutylacetyloxyethyl,cyclobutylpropionyloxyethyl, cyclopentylacetyloxyethyl,cyclopentylpropionyloxyethyl, cyclopentylbutyryloxyethyl,cyclohexylacetyloxyethyl, and cyclohexylpropionyloxyethyl. Preferably R⁶is 3-cyclopentylpropionyloxymethyl. It is preferred that in suchcompounds R⁷ is preferably C₁₋₈ alkyl, more preferably ethyl ortert-butyl, and most preferably tert-butyl.

A yet further group of suitable compounds include those where R⁶ isselected from the group consisting of —C₁₋₂alkyleneOC(O)OR⁷ preferablywhere R⁶ is CH₂OC(O)OR⁷, and where R⁷ is C₁₋₈ alkyl for example methyl,ethyl, n-propyl, isopropyl, butyl, tert-butyl, which may in turn beoptionally further substituted. Examples of such so substituted R⁶groups include methoxycarbonyloxymethyl, methoxycarbonyloxyethyl,ethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl,propoxycarbonyloxymethyl, propoxycarbonyloxyethyl,isopropoxycarbonyloxymethyl, isopropoxycarbonyloxyethyl,butoxycarbonyloxymethyl, butoxycarbonyloxyethyl,isobutoxycarbonyloxymethyl, isobutoxycarbonyloxyethyl,pentyloxycarbonyloxymethyl, pentyloxycarbonyloxyethyl,2-methylbutoxycarbonyloxymethyl, 2-methyl butoxycarbonyloxyethyl,3-methylbutoxycarbonyloxymethyl, 3-methylbutoxycarbonyloxyethyl,2,2-dimethylpropoxycarbonyloxymethyl,2,2-dimethylpropoxycarbonyloxyethyl, hexyloxycarbonyloxymethyl,hexyloxycarbonyloxyethyl. Further suitable examples of compounds whereR⁶ is selected from the group consisting of —C₁₋₂alkyleneOC(O)OR⁷,preferably where R⁶ is CH₂OC(O)OR⁷, also include those where R⁷ isselected from the group consisting of C₃₋₆ cycloalkyl for examplecyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; C₁₋₄ alkylene(C₃₋₆cycloalkyl) for example cyclopropylmethyl, cyclopropylethyl,cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl,cyclohexylmethyl, cyclohexylethyl; C₁₋₆ haloalkyl for exampletrifluoromethyl, and 2,2,2-trifluoroethyl; and C₀₋₆ alkylphenyl forexample phenyl which is optionally further substituted to form forexample 4-methoxyphenyl, 4-trifluoromethylphenyl-4-methoxybenzyl.Examples of such so substituted R⁶ groups includecyclopropyloxycarbonyloxymethyl, cyclobutyloxycarbonyloxymethyl,cyclopentyloxycarbonyloxymethyl or cyclohexyloxycarbonyloxymethylcyclopropyloxycarbonyloxyethyl, cyclobutyloxycarbonyloxyethyl,cyclopentyloxycarbonyloxyethyl or cyclohexyloxycarbonyloxyethyl; C₁₋₄alkylene(C₃₋₆ cycloalkyl) for examplecyclopropylmethyloxycarbonyloxymethyl,cyclopropylethyloxycarbonyloxymethyl,cyclobutylmethyloxycarbonyloxymethyl,cyclobutylethyloxycarbonyloxymethyl,cyclopentylmethyloxycarbonyloxymethyl,cyclopentylethyloxycarbonyloxymethyl,cyclohexylmethyloxycarbonyloxymethyl,cyclohexylethyloxycarbonyloxymethyl,cyclopropylmethyloxycarbonyloxyethyl,cyclopropylethyloxycarbonyloxyethyl,cyclobutylmethyloxycarbonyloxyethyl, cyclobutylethyloxycarbonyloxyethyl,cyclopentylmethyloxycarbonyloxyethyl,cyclopentylethyloxycarbonyloxyethyl,cyclohexylmethyloxycarbonyloxyethyl, cyclohexylethyloxycarbonyloxyethyl;C₁₋₆ haloalkyl for example trifluoromethyloxycarbonyloxymethyl, and2,2,2-trifluoroethyloxycarbonyloxymethyl,trifluoromethyloxycarbonyloxyethyl, and2,2,2-trifluoroethyloxycarbonyloxyethyl; and C₀₋₆ alkylphenyl forexample phenyloxycarbonyloxymethyl which is optionally furthersubstituted to form for example 4-methoxyphenyloxycarbonyloxymethyl,4-trifluoromethylphenyloxycarbonyloxymethyl,4-methoxybenzyloxycarbonyloxymethyl.

A still yet further group of suitable compounds include those where R⁶is selected from the group consisting of —C₀₋₂alkyleneC(O)OR⁷,preferably where R⁶ is C(O)OR⁷, and where R⁷ is C₁₋₈ alkyl for examplemethyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, which may in turnbe optionally further substituted. Examples of such so substituted R⁶groups include methoxycarbonyl, methoxycarbonylmethyl,methoxycarbonylethyl, ethoxycarbonyl, ethoxycarbonylmethyl,ethoxycarbonylethyl, propoxycarbonyl, propoxycarbonylmethyl,propoxycarbonylethyl, isopropoxycarbonyl, isopropoxycarbonylmethyl,isopropoxycarbonylethyl, butoxycarbonyl, butoxycarbonylmethyl,butoxycarbonylethyl, isobutoxycarbonyl, isobutoxycarbonylmethyl,isobutoxycarbonylethyl, pentyloxycarbonyl, pentyloxycarbonylmethyl,pentyloxycarbonylethyl, 2-methylbutoxycarbonyl,2-methylbutoxycarbonylmethyl, 2-methylbutoxycarbonylethyl,3-methylbutoxycarbonyl, 3-methylbutoxycarbonylmethyl,3-methylbutoxycarbonylethyl, 2,2-dimethylpropoxycarbonyl,2,2-dimethylpropoxycarbonylmethyl, 2,2-dimethylpropoxycarbonylethyl,hexyloxycarbonyl, hexyloxycarbonylmethyl, hexyloxycarbonylethyl. Furthersuitable examples of compounds include those where R⁶ is selected fromthe group consisting of —C₀₋₂alkyleneC(O)OR⁷, preferably where R⁶ isC(O)OR⁷, also include those where R⁷ is selected from the groupconsisting of C₀₋₆ alkylphenyl for example phenyl which in turn isoptionally substituted to form for example 4-methoxy phenyl,4-trifluoromethyl phenyl. Examples of such so substituted R⁶ groupsinclude phenyloxycarbonyl, phenyloxycarbonylmethyl,phenyloxycarbonylethyl.

An even further group of suitable compounds include those where R⁶ isselected from the group consisting of —C₁₋₂alkyleneOC(O)NHR⁷, preferablywhere R⁶ is CH₂OC(O)NHR⁷, and where R⁷ is selected from the groupconsisting of C₁₋₈ alkyl for example methyl, ethyl, n-propyl, isopropyl,butyl, tert-butyl; C₃₋₆ cycloalkyl for example cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl; C₁₋₆ haloalkyl for example trifluoromethyl,and trifluoroethyl; and C₀₋₆ alkylphenyl for example phenyl,phenylmethyl or phenylethyl which C₀₋₆ alkylphenyl is optionallysubstituted to form for example 4-methoxyphenyl,4-trifluoromethylphenyl, 2,4-dichlorophenyl, 4-methoxyphenylmethyl,4-trifluoromethylphenylmethyl, 2,4-dichlorophenylmethyl,4-methoxyphenylethyl, 4-trifluoromethylphenylethyl, or2,4-dichlorophenylethyl.

Preferred are those compounds where R⁶ is selected from the groupconsisting of hydrogen, —C₀₋₂alkyleneR⁷ and —C₁₋₂alkyleneOC(O)R⁷ andwhere R⁷ is selected from the group consisting of C₁₋₈ alkyl. Even morepreferred compounds are those where R⁶ is hydrogen.

Preferably, each R⁸ and R⁹ are independently selected from the groupconsisting of hydrogen; C₁₋₄ alkyl eg methyl or ethyl, preferablymethyl; C₁₋₄ haloalkyl for example trifluoromethyl, trichloromethyl,trichloroethyl or trifluoroethyl, preferably trifluoromethyl; C₁₋₄alkoxy for example methoxy or ethoxy, preferably methoxy; and C₀₋₄alkylenephenyl for example phenyl, phenylmethyl or phenylethyl, but withthe proviso that R⁸ and R⁹ are not both hydrogen. More preferably eachR⁸ and R⁹ are independently selected from the group consisting ofhydrogen and C₁₋₄ alkyl eg methyl or ethyl, preferably methyl but againwith the proviso that R⁸ and R⁹ are not both hydrogen. Most preferablyR⁸ is methyl and R⁹ is hydrogen.

Suitably when either one or more of R⁸ or R⁹ are phenyl, the phenylgroup is optionally substituted with one or more substitutents selectedfrom the group consisting of fluoro, chloro, methoxy or trifluoromethyl.

Suitably when R⁸ and R⁹ together with the carbon to which they areattached may form a three to six membered carbocyclic, saturated ring itis preferred that the ring is a three membered ring.

Preferably each of R¹¹ and R¹² are independently selected from the groupconsisting of hydrogen, C₁₋₂ alkyl eg methyl or ethyl, preferablymethyl, and C₁₋₂ alkoxy for example methoxy or ethoxy, preferablymethoxy. More preferably at least one of R¹¹ and R¹² is hydrogen. Mostpreferably both of R¹¹ and R¹² are hydrogen.

A further group of suitable compounds of the present invention are thoseof formula (LV) where:

-   each of R¹, R², R³, R⁴, R⁵ are independently selected from hydrogen    and C₁₋₄ alkyl eg methyl or ethyl, preferably methyl;-   each R⁸ and R⁹ are independently selected from the group consisting    of hydrogen and C₁₋₄ alkyl eg methyl or ethyl, preferably methyl;    and-   each R¹¹ and R¹² are hydrogen or a pharmaceutically acceptable salt    or a prodrug thereof. Preferably, in compounds of formula (LV): R¹,    R² and R⁸ are selected from C₁₋₄ alkyl eg methyl or ethyl,    preferably methyl, R³, R⁴, R⁵ and R⁹ are H.

It will be understood that throughout the application all references toformula (I) apply equally to compounds of the formula (LV).

Furthermore, it will be understood that all the suitable groups andpreferences applied to R¹-R¹², R^(a), R^(b) and n for formula (I) applyequally to compounds of the formula (LV).

A further group of preferred compounds are the compounds of formula(XXXX)

wherein R¹ to R⁵ are selected from hydrogen, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl and CN, and R⁸ is C₁₋₃ alkyl. Preferably, at least two of R¹to R⁵ are hydrogen, and more preferably at least three of R¹ to R⁵ arehydrogen. Preferably, the groups from R¹ to R⁵ that are not hydrogen areselected from chloro, fluoro, methyl, ethyl, difluoromethyl andtrifluoromethyl, and more preferably from fluoro, chloro and methyl.Preferably R⁸ is methyl or ethyl, and more preferably R⁸ is methyl.

A further group of preferred compounds are the compounds of formula(XXXXI)

wherein R¹ to R⁵ are selected from hydrogen, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl and CN, R⁷ is phenyl optionally substituted by one or moregroups selected from cyano, nitro, halo, formyl, hydroxy, C(O)OH, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ alkyleneC₃₋₆cycloalkyl, C₁₋₄ alkoxy, —C(O)OC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, pyrazolyl, triazolyl, amino, C₁₋₄ alkylamino, and C₁₋₄dialkylamino, and R⁸ is C₁₋₃ alkyl. Preferably, at least two of R¹ to R⁵are hydrogen, and more preferably at least three of R¹ to R⁵ arehydrogen. Preferably, the groups from R¹ to R⁵ that are not hydrogen areselected from chloro, fluoro, methyl, ethyl, difluoromethyl andtrifluoromethyl, and more preferably from fluoro, chloro and methyl.Preferably R⁷ is phenyl optionally substituted by one or two groupsselected from cyano, chloro, fluoro, hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxyand C₁₋₂ haloalkyl. Preferably R⁸ is methyl or ethyl, and morepreferably R⁸ is methyl.

A further group of preferred compounds are the compounds of formula(XXXXII)

wherein R¹ to R⁵ are selected from hydrogen, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl and CN, R⁷ is selected from C₁₋₃alkylenephenyl optionallysubstituted by on the phenyl ring by one or more groups selected fromcyano, halo, hydroxy, C(O)OH, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄alkyleneC₃₋₆ cycloalkyl, C₁₋₄ alkoxy, —C(O)OC₁₋₄ alkyl, C₁₋₄ haloalkyl,and C₁₋₄ haloalkoxy, C₁₋₈ alkyl optionally substituted by one or twoC₁₋₄ alkoxy groups, C₃₋₆ cycloalkyl, C₁₋₃alkyleneC₃₋₆cycloalkyl, andC₁₋₆ haloalkyl, and R⁸ is C₁₋₃ alkyl. Preferably, at least two of R¹ toR⁵ are hydrogen, and more preferably at least three of R¹ to R⁵ arehydrogen. Preferably, the groups from R¹ to R⁵ that are not hydrogen areselected from chloro, fluoro, methyl, ethyl, difluoromethyl andtrifluoromethyl, and more preferably from fluoro, chloro and methyl.Preferably R⁷ is C₁₋₈alkyl or C₁₋₆haloalkyl. Preferably R⁸ is methyl orethyl, and more preferably R⁸ is methyl.

A further group of preferred compounds are the compounds of formula(XXXXIII)

wherein R¹ to R⁵ are selected from hydrogen, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl and CN, R⁷ is selected from C₁₋₃alkylenephenyl optionallysubstituted by on the phenyl ring by one or more groups selected fromcyano, halo, hydroxy, C(O)OH, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄alkyleneC₃₋₆ cycloalkyl, C₁₋₄ alkoxy, —C(O)OC₁₋₄ alkyl, C₁₋₄ haloalkyl,and C₁₋₄ haloalkoxy, C₁₋₈ alkyl optionally substituted by one or twoC₁₋₄ alkoxy groups, C₃₋₆ cycloalkyl, C₁₋₃alkyleneC₃₋₆cycloalkyl, andC₁₋₆ haloalkyl, and R⁸ is C₁₋₃ alkyl. Preferably, at least two of R¹ toR⁵ are hydrogen, and more preferably at least three of R¹ to R⁵ arehydrogen. Preferably, the groups from R¹ to R⁵ that are not hydrogen areselected from chloro, fluoro, methyl, ethyl, difluoromethyl andtrifluoromethyl, and more preferably from fluoro, chloro and methyl.Preferably R⁷ is C₁₋₈alkyl or C₁₋₆haloalkyl. Preferably R⁸ is methyl orethyl, and more preferably R⁸ is methyl.

A further group of preferred compounds are the compounds of formula(XXXXIV)

wherein R¹ to R⁵ are selected from hydrogen, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl and CN, R⁷ is selected from C₁₋₃alkylenephenyl optionallysubstituted by on the phenyl ring by one or more groups selected fromcyano, halo, hydroxy, C(O)OH, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄alkyleneC₃₋₆ cycloalkyl, C₁₋₄ alkoxy, —C(O)OC₁₋₄ alkyl, C₁₋₄ haloalkyl,and C₁₋₄ haloalkoxy, C₁₋₈ alkyl optionally substituted by one or twoC₁₋₄ alkoxy groups, C₃₋₆ cycloalkyl, C₁₋₃alkyleneC₃₋₆cycloalkyl, andC₁₋₆ haloalkyl, and R⁸ is C₁₋₃ alkyl. Preferably, at least two of R¹ toR⁵ are hydrogen, and more preferably at least three of R¹ to R⁵ arehydrogen. Preferably, the groups from R¹ to R⁵ that are not hydrogen areselected from chloro, fluoro, methyl, ethyl, difluoromethyl andtrifluoromethyl, and more preferably from fluoro, chloro and methyl.Preferably R⁷ is C₁₋₈alkyl or C₁₋₆haloalkyl, and more preferably R⁷ isisobutyl. Preferably R⁸ is methyl or ethyl, and more preferably R³ ismethyl.

Preferred individual compounds of the invention are selected from thecompounds of the Examples described herein.

More preferred individual compounds of the invention are selected from:

-   2-[(2,3-dimethylphenyl)(methoxy)methyl]-1H-imidazole;-   2-[1-(2,5-dimethylphenyl)ethyl]-1H-imidazole;-   2-[1-(2,4-dimethylphenyl)ethyl]-1H-imidazole;-   2-[1-(3,4-dimethylphenyl)ethyl]-1H-imidazole;-   2-{1-[2-(trifluoromethyl)phenyl]ethyl}-1H-imidazole;-   (2,3-dimethylphenyl)(1H-imidazol-2-yl)methanol;-   2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl pivalate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl propionate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    3-methylbutanoate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl butyrate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    3-cyclopentylpropanoate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl heptanoate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl pentanoate-   2-[1-(4-chloro-3-methylphenyl)ethyl]-1H-imidazole-   2-[1-(3,5-dimethylphenyl)ethyl]-1H-imidazole-   1-benzyl-2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    4-methoxybenzyl carbonate-   1-(cyclopropylmethyl)-2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-   2-[1-(2,3-dimethylphenyl)ethyl]-1-methyl-1H-imidazole-   cyclopropylmethyl    {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl carbonate-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    3-methylbutyl carbonate-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl isopropyl    carbonate-   cyclobutyl {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    carbonate-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    2,2,2-trifluoroethyl carbonate-   2-[1-(2,3-dimethylphenyl)ethyl]-1-ethyl-1H-imidazole-   2-[1-(2,3-dimethylphenyl)ethyl]-1-(4-methoxybenzyl)-1H-imidazole-   2-[1-(2,3-dimethylphenyl)ethyl]-1-(methoxymethyl)-1H-imidazole-   2-[1-(2,3-dimethylphenyl)ethyl]-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-   4-fluorophenyl    2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate-   isobutyl 2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate-   isopropyl 2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate-   2-[1-(3-methylphenyl)ethyl]-1H-imidazole    or a pharmaceutically acceptable salt or prodrug thereof.

More preferred individual compounds of the present invention areselected from:

-   2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;-   2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;-   2-[(1R)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl pivalate;-   {2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpivalate;-   {2-[(1R)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpivalate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl propionate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    3-methylbutanoate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl butyrate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    3-cyclopentylpropanoate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl heptanoate;-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl pentanoate-   2-{1-[2-(trifluoromethyl)phenyl]ethyl}-1H-imidazole;-   2-[1-(2,5-dimethylphenyl)ethyl]-1H-imidazole-   2-[1-(4-chloro-3-methylphenyl)ethyl]-1H-imidazole-   2-[1-(3,5-dimethylphenyl)ethyl]-1H-imidazole-   1-benzyl-2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    4-methoxybenzyl carbonate-   1-(cyclopropyl methyl)-2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-   2-[1-(2,3-dimethylphenyl)ethyl]-1-methyl-1H-imidazole-   cyclopropylmethyl    {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl carbonate-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    3-methylbutyl carbonate-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl isopropyl    carbonate-   cyclobutyl {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    carbonate-   {2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl    2,2,2-trifluoroethyl carbonate-   2-[1-(2,3-dimethylphenyl)ethyl]-1-ethyl-1H-imidazole-   2-[1-(2,3-dimethylphenyl)ethyl]-1-(4-methoxybenzyl)-1H-imidazole-   2-[1-(2,3-dimethylphenyl)ethyl]-1-(methoxymethyl)-1H-imidazole-   2-[1-(2,3-dimethylphenyl)ethyl]-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-   4-fluorophenyl    2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate-   isobutyl 2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate-   isopropyl 2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate-   2-[1-(3-methylphenyl)ethyl]-1H-imidazole    or a pharmaceutically acceptable salt or prodrug thereof.

Even more preferred compounds of the present invention are2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, and{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl pivalate, or apharmaceutically acceptable salt or prodrug thereof.

The most preferred compound of the present invention is2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, or a pharmaceuticallyacceptable salt or prodrug thereof.

Included within the scope of the present invention are all stereoisomerssuch as enantiomers and diasteromers, all geometric isomers andtautomeric forms of the compounds of formula (I), including compoundsexhibiting more than one type of isomerism, and mixtures of one or morethereof. Also included are acid addition or base salts wherein thecounterion is optically active, for example, D-lactate or L-lysine, orracemic, for example, DL-tartrate or DL-arginine.

It is to be understood that compounds of formula (I) may contain one ormore asymmetric carbon atoms, thus compounds of the invention can existas two or more stereoisomers. In particular it will be understood thatwhen R⁸ and R⁹ are different substitutents a stereocentre exists at thecarbon atom to which they are attached—the benzylic carbon. Suitablecompounds for use in this invention include those where the absolutestereochemistry at the benzylic carbon has the “S configuration”.Further suitable compounds for use in this invention include those wherethe absolute stereochemistry at the benzylic carbon has the “Rconfiguration”. Such stereoisomers can be resolved and identified by oneskilled in the art using known techniques.

The present invention includes the individual stereoisomers of thecompounds of formula (I) together with mixtures thereof. Preferredcompounds of formula (I) include those of formula (IA) and formula (IB)which possess the stereochemistry shown below.

It will be understood that throughout the application all references toformula (I) apply equally to compounds of the formulae (IA) and (IB).

Furthermore, it will be understood that all the suitable groups andpreferences applied to R¹-R¹², R^(a), R^(b) and n for formula (I) applyequally to compounds of the formulae (IA) and (IB).

In one particular embodiment of the invention preferred compounds arethose of the formula (IA).

In one particular embodiment of the invention preferred compounds arethose of the formula (IB).

Preferred compounds of the present invention include2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole,2-[(1R)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole,{2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpivalate,{2-[(1R)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpivalate ora pharmaceutically acceptable salt or prodrug thereof.

Even more preferred compounds of the present invention are2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole,2-[(1R)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, or a pharmaceuticallyacceptable salt or prodrug thereof with the formulae shown below.

Most preferred is 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole.

Geometric isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallisation.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor, stereoselective synthesis from a prochiral precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, fractional crystallization or chiral high pressureliquid chromatography (HPLC). Reference is made herein to “Enantiomers,Racemates and Resolutions” J. Jacques and A. Collet, published by Wiley,NY, 1981; and “Handbook of Chiral Chemicals” chapter 8, Eds D. Ager andM. Dekker, ISBN: 0-8247-1058-4.

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula (I) contains an acidic or basicmoiety, an acid or base such as tartaric acid or 1-phenylethylamine. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, typically heptane or hexane, containing from 0 to 50%isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine,typically 0.1% diethylamine. Concentration of the eluant affords theenriched mixture.

Stereoisomeric conglomerates may be separated by conventional techniquesknown to those skilled in the art—see, for example, “Stereochemistry ofOrganic Compounds” by E L Eliel (Wiley, New York, 1994).

In the compounds according to formula (I) the term ‘halo’ means a groupselected from fluoro, chloro, bromo or iodo.

Alkyl, alkylene, alkenyl, alkynyl and alkoxy groups, containing therequisite number of carbon atoms, can be unbranched or branched.Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl and t-butyl. Examples of alkoxy include methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy and t-butoxy.Examples of alkylene include —CH₂—, —CH(CH₃)— and —C₂H₄—. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

For the avoidance of doubt, it will be understood that throughout theapplication all references to pharmaceutically acceptable compoundsincludes references to veterinarily acceptable compounds oragriculturally acceptable compounds. Furthermore it will be understoodthat throughout the application all references to pharmaceuticalactivity includes references to veterinary activity or agriculturalactivity.

Pharmaceutically acceptable salts of the compounds of formula (I)include the acid addition and base salts thereof. Suitable acid additionsalts are formed from acids, which form non-toxic salts. Examplesinclude the acetate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts. Suitable basesalts are formed from bases which form non-toxic salts. Examples includethe aluminium, arginine, benzathine, calcium, choline, diethylamine,diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium,sodium, tromethamine and zinc salts.

The pharmaceutically, veterinarily and agriculturally acceptable acidaddition salts of certain of the compounds of formula (I) may also beprepared in a conventional manner. For example, a solution of a freebase may be treated with the appropriate acid, either neat or in asuitable solvent, and the resulting salt isolated either by filtrationor by evaporation under reduced pressure of the reaction solvent. For areview on suitable salts, see “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

The compounds of the invention may exist in both unsolvated and solvatedforms. The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water. Pharmaceuticallyacceptable solvates in accordance with the invention include thosewherein the solvent of crystallization may be isotopically substituted,e.g. D₂O, d₆-acetone, d₆-DMSO.

Hereinafter and throughout the application all references to compoundsof formula (I) include references to salts, solvates and complexesthereof and to solvates and complexes of salts thereof.

As stated, the invention includes all polymorphs of the compounds offormula (I) as hereinbefore defined.

Included within the scope of the invention are complexes such asclathrates, drug-host inclusion complexes wherein, in contrast to theaforementioned solvates, the drug and host are present in stoichiometricor non-stoichiometric amounts. Also included are complexes of the drugcontaining two or more organic and/or inorganic components which may bein stoichiometric or non-stoichiometric amounts. The resulting complexesmay be ionised, partially ionised, or non-ionised. For a review of suchcomplexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August1975).

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of formula (I) wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number usuallyfound in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include isotopes of hydrogen, such as ²H and ³H, carbon, suchas ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as³⁵S.

Within the scope of the invention are so-called ‘prodrugs’ of thecompounds of formula (I). Thus certain derivatives of compounds offormula (I) which may have little or no pharmacological activitythemselves can, when administered into or onto the body of an animal, beconverted by the host or parasite into compounds of formula (I) havingthe desired activity, for example, by hydrolytic or enzymatic cleavage.

Such derivatives are referred to as ‘prodrugs’. It will be appreciatedthat certain compounds of formula (I) may themselves act as pro-drugs ofother compounds of formula (I). Further information on the use ofprodrugs may be found in ‘Pro-drugs as Novel Delivery Systems, Vol. 14,ACS Symposium Series (T Higuchi and W Stella) and ‘BioreversibleCarriers in Drug Design’, Pergamon Press, 1987 (ed. E B Roche, AmericanPharmaceutical Association).

Prodrugs in accordance with the invention can, for example, be producedby replacing appropriate functionalities present in the compounds offormula (I) with certain moieties known to those skilled in the art as‘pro-moieties’ as described, for example, in “Design of Prodrugs” by HBundgaard (Elsevier, 1985).

Some examples of prodrugs in accordance with the invention include:

-   (i) where the compound of formula (I) contains a carboxylic acid    functionality (—COOH), an ester thereof, for example, replacement of    the hydrogen with (C₁-C₈)alkyl;-   (ii) where the compound of formula (I) contains an alcohol    functionality (—OH), an ether thereof, for example, replacement of    the hydrogen with (C₁-C₆)alkanoyloxymethyl; and-   (iii) where the compound of formula (I) contains a primary or    secondary amino functionality (—NH₂ or —NHR where R≠H), an amide    thereof, for example, replacement of one or both hydrogens with    (C₁-C₁₀)alkanoyl.

Prodrugs in accordance with the invention can, for example, be producedby reacting compounds of formula (I) wherein R⁶ is H with certainmoieties known to those skilled in the art as ‘pro-drug moieties’ asdescribed, for example, in “Design of Prodrugs” by H Bundgaard(Elsevier, 1985); “Design and application of prodrugs,” Textbook of DrugDesign and Discovery, (3rd Edition), 2002, 410-458, (Taylor and FrancisLtd., London); and references therein. Examples of substituents include:alkyl amines, aryl amines, amides, ureas, carbamates, carbonates,imines, enamines, imides, sulfenamides, and sulfonamides. Thehydrocarbon portion of these groups contain C₁₋₆ alkyl, phenyl,heteroaryl such as pyridyl, C₂₋₆ alkenyl, and C₃₋₈ cycloalkyl; whereineach of the above groups may include one or more optional substituentswhere chemically possible independently selected from: halo; hydroxy;C₁₋₆ alkyl, C₁₋₆ haloalkyl and C₁₋₆ alkoxy.

Further examples of replacement groups in accordance with the foregoingexample and examples of other prodrug types may be found in theaforementioned references.

A prodrug that is administered to a test animal and metabolized by thehost according to the invention can be readily identified by sampling abody fluid for a compound of formula (I).

Finally, certain compounds of formula (I) may themselves act as prodrugsof other compounds of formula (I).

In a further aspect, the present invention provides processes for thepreparation of a compound of formula (I), or a pharmaceutically,veterinarily or agriculturally acceptable salt thereof, or apharmaceutically, veterinarily or agriculturally acceptable solvate(including hydrate) of either entity, as illustrated below.

The following processes are illustrative of the general syntheticprocedures which may be adopted in order to obtain the compounds of theinvention.

It will be apparent to those skilled in the art that sensitivefunctional groups may need to be protected and deprotected duringsynthesis of a compound of the invention. This may be achieved byconventional methods, for example as described in “Protective Groups inOrganic Synthesis” by TW Greene and PGM Wuts, John Wiley & Sons Inc(1999), and references therein. Thus, when one or more of R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁵ and R¹⁶ contain reactivefunctional groups then additional protection may be provided accordingto standard procedures during the synthesis of compounds of formula (I).In the processes described below, for all synthetic precursors used inthe synthesis of compounds of formula (I), the definitions of R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁵ and R¹⁶, wherein R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁵ and R¹⁶, are as definedfor formula (I), are intended to optionally include suitably protectedvariants, P¹, P², P³, P⁴, P⁵, P⁶, P⁷, P⁸, P⁹, P¹⁰, P¹¹, P¹², P¹⁵ andP¹⁶. Such suitable protecting groups for these functionalities aredescribed in the references listed below and the use of these protectinggroups where needed is specifically intended to fall within the scope ofthe processes described in the present invention for producing compoundsof formula (I) and its precursors. When suitable protecting groups areused, then these will need to be removed to yield compounds of formula(I). Deprotection can be effected according to standard proceduresincluding those described in the references listed below. When R⁶ is aprotecting group it is preferred that it is chosen from benzyl,p-methoxybenzyl, diethoxymethyl, allyl and trityl.

Compounds of formula (I) may be obtained from other compounds of formula(I) by standard procedures such as electrophilic or nucleophilicsubstitution, organometallic catalysed cross coupling reactions andfunctional group interconversions known to those skilled in the art. Forexample, compounds of formula (I) in which one or more of R¹, R², R³, R⁴and R⁵ are CO₂R^(c) wherein R^(c)=alkyl, may be transformed intocompounds of formula (I) in which one or more of R¹, R², R³, R⁴ and R⁵are CO₂R^(d) wherein R^(d)=NH₂ upon treatment with ammonium hydroxide at85° C. for 2 h. Similarly compounds of formula (I) wherein one or moreof R¹, R², R³, R⁴ and R⁵ are CO₂R^(d) wherein R^(d)=NH₂ upon treatmentwith a dehydrating agent such as thionyl chloride at low temperatures inan anhydrous solvent such as N,N-dimethylformamide produce thecorresponding nitrile compound.

Compounds of formula (I), wherein R⁸ is C₁-C₄ alkyl, R⁹, R¹¹ and R¹² arehydrogen and R⁶ is hydrogen or alkyl and R¹, R², R³, R⁴ and R⁵ are asdefined previously

may be synthesised from compounds of formula (II) using standardhydrogenation procedures. For example, compounds of formula (II) whereinR^(a) is hydrogen, and R^(b) is hydrogen or alkyl may be reduced tocompounds of formula (I) in a suitable protic solvent such as methanolor propan-2-ol under a hydrogen atmosphere at temperatures up to 60° C.and elevated pressure up to 300 psi in the presence of 10% palladium oncarbon or Freiborg activated 10% palladium on carbon for up to 72 h.

Compounds of formula (I) in which one or more of R¹, R², R³, R⁴ and R⁵are optionally halo, and the remainder of R¹, R², R³, R⁴ and R⁵ are aspreviously defined, may be accessed from compounds of formula (II) inwhich one or more of R¹, R², R³, R⁴ and R⁵ are optionally halo byhydrogenation procedures. Thus, compounds of formula (II) may be reducedto give compounds of formula (I) under a hydrogen atmosphere attemperatures up to 60° C. and elevated pressure up to 200 psi in thepresence of 10% palladium on carbon and a chelating agent such as zincbromide in a standard protic solvent such as methanol or propan-2-ol.

Alternatively, compounds of formula (I) may be obtained from compoundsof formula (II) by transfer hydrogenation conditions. For example,ammonium formate or formic acid or ammonium formate in the presence offormic acid may be used to generate an in situ source of hydrogen whichwhen in the presence of a hydrogenation catalyst such as 10% palladiumon carbon in an alcoholic solvent such as propan-2-ol, for 2-3 hours attemperatures up to 80° C. can be used to effect the transformation ofcompounds of formula (II) to compounds of formula (I). Optionallyreactions using formic acid as the hydrogen source may be performedwithout alcoholic solvents.

Stereoselective hydrogenations may be performed to yield a preferredstereoisomer using chiral catalysts, in accordance with standard organicchemistry textbooks or literature precedent. For example there are manyknown homogeneous and heterogeneous catalytic methods using transitionmetals such as palladium, rhodium and ruthenium. One particularlypreferred catalyst is bis(norbornadiene)rhodium(I) tetrafluoroborate.Enantiopure ligands that have been utilised to effect enantioselectivehydrogenations have been referenced in the literature and illustrativeexamples of homochiral ligands include phospholanes such as Duphos andits analogues, ferrocenyl ligands such as Josiphos,1-[(R)-2-diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine,biphenyl ligands such as(+/−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) andmiscellaneous ligands such as Prophos, Diamp, Bicp, Monophos. Referencesproviding details of enantioselective hydrogenations include Y.Yamanori, T. Imamoto, Reviews on Heteroatom Chemistry, 1999, 20, 227; T.Clark, C. Landis, Tetrahedron: Asymmetry, 2004, 15, 14, 2123; H. Blaser,Topics in Catalysis, 2002, 19, 1, 3; H. Blaser et al, Synthetic Methodsof organometallic and inorganic chemistry, 2002, 10, 78; Pure andApplied Chemistry, 1999, 71, 8, 1531; Pure and Applied Chemistry, 1998,70, 8, 1477; U. Berens et al, Speciality Chemicals, 2000, 20, 6, 210; M.T. Reetz, Pure and Applied Chemistry, 1999, 71, 8, 1503; D. J. Baystonet al, Speciality Chemicals, 1998, 18, 5, 224; C. Saluzzo and M.Lemaire, Advanced Synthesis and Catalysis, 2002, 344, 9, 915; H.Kumobayashi, Synlett, 2001, (Spec Issue) 1055.

Thus, enantiomerically enriched compounds of formula (I) may be obtainedfrom achiral compounds of formula (II) by stereoselective hydrogenation.For example, compounds of formula (II) wherein R^(a) is hydrogen, andR^(b) is hydrogen or alkyl may be reduced to compounds of formula (I) ina suitable protic solvent such as methanol under a hydrogen atmosphereat ambient temperatures and elevated pressure up to 60 psi in thepresence of a rhodium catalyst such as bis(norbornadiene)rhodium(I)tetrafluoroborate and chiral ligand such as1-[(R)-2-diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine togive optically enriched compounds of formula (I).

Chiral resolution can be utilised to enhance the enantiomeric purity ofcompounds of formula (I). For example, an acid salt can beenantioselectively formed upon addition of an enantiomerically purechiral acid such as di-p-toluoyl-L-tartaric acid in a suitable proticsolvent such as methanol. Using this process one enantiomerpreferentially forms a crystalline salt which can be removed byfiltration whereas the other enantiomer remains in the mother liquor.Upon separately basifying the salt and mother liquor with a suitablebase such as sodium hydroxide (1N), the enantiomers are resolved to giveseparated optically enriched compounds of formula (I).

Alternatively, racemic compounds of formula (I) may be resolved usingchiral HPLC procedures, known to those skilled in the art, to giveenantiomerically pure compounds of formula (I).

Compounds of formula (II) wherein R⁶ is a protecting group such asbenzyl or substituted benzyl e.g. p-methoxybenzyl, may be deprotectedand reduced under hydrogenation conditions to give compounds of formula(I) wherein R⁶ is hydrogen.

Imidazole ring formation can also be utilised to access compounds offormula (I), other synthetic methods are precedented in textbooks andthe literature. One illustrative example is from desirably substitutedphenylacetonitrile reactants, for example a compound such as2-(2,3-dimethylphenyl)propanenitrile may be reacted with anappropriately substituted ethylenediamine for example, thep-toluenesulfonic acid salt of ethylenediamine at elevated temperaturesranging from 140°-180° C. to form the compound of formula (I) whereinR¹, R² and R⁸ are methyl and R³, R⁴, R⁵, R⁶ and R⁹, R¹¹ and R¹² arehydrogen.

Another example of imidazole ring formation is from the reaction ofsuitably 2-substituted 2-aryl-1,1-dibromoethenes and an appropriatelysubstituted ethylenediamine at room temperature to give the intermediate2-substituted 2-arylmethylimidazoline. Standard oxidation proceduressuch as Swern oxidation can transform the intermediate 2-substituted2-arylmethylimidazoline into compounds of formula (I).

Compounds of formula (II) may be prepared by Wittig chemistry by thereaction of a compound of formula (X) with the appropriatealkylphosphonium salt-derived phosphorus ylid. For example treatment ofa methyltriphenylphosphonium halide with a strong base in a suitablesolvent, followed by the addition of (X), will produce a compound offormula (II) wherein both R^(a) and R^(b) are hydrogen. Preferably thebase reagent is a solution of n-butyllithium in hexane, the solvent isether or tetrahydrofuran and the reaction is conducted at from aboutroom temperature to about 35° C.

Compounds of formula (II) may undergo functional group interconversioninto other compounds of formula (II). For example, wherein one or moreof R¹, R², R³, R⁴ and R⁵ are bromo or iodo, and R⁶ is protected with asuitable protecting group such as benzyl, palladium catalysed couplingreactions such as Stille, Heck and Suzuki coupling reactions may beeffected. For example, treatment of such organohalide compounds offormula (II) with a suitable boronic acid such as an alkyl or arylboronic acid, in an inert solvent such as toluene, in the presence of asuitable base such as potassium phosphate, a suitable phosphine ligandsuch as tricyclohexylphosphine and palladium acetate under an inertatmosphere at elevated temperatures up to 120° C. for up to 18 hprovides the corresponding alkylated or arylated compound of formula(II). Similarly, compounds of formula (II) wherein one or more of R¹,R², R³, R⁴ and R⁵ are bromo or iodo, and R⁶ is protected with a suitableprotecting group such as benzyl, may undergo transmetallation reactionwith a palladium catalyst such as[1,1-bis(diphenylphosphino)ferrocene]palladium (II) chloride followed bycross coupling with a suitable boronic anhydride such astrialkylboroxine under an inert atmosphere, in the presence of a mildbase such as sodium carbonate and a suitable inert solvent such asdioxane and water at elevated temperatures up to 120° C. Alternatively,compounds of formula (II) wherein one or more of R¹, R², R³, R⁴ and R⁵are bromo or iodo, and R⁶ is protected with a suitable protecting groupsuch as benzyl, may undergo nucleophilic substitution reactions. Forexample, nitrile compounds may be formed upon treatment of such a halocompound of formula (II) in a polar solvent such asN,N-dimethylacetamide with a cyanide source such as copper cyanide attemperatures up to 150° C. for 3 days to give the corresponding compoundof formula (II) wherein one or more of R¹, R², R³, R⁴ and R⁵ are cyano,and R⁶ is protected with a suitable protecting group such as benzyl.Nitrile compounds of formula (II) may also be formed from thecorresponding halo compound of formula (II) upon treatment with acyanide source such as sodium cyanide in the presence of a suitabletransmetallating agent such as nickel bromide in a polar solvent such asN-methylpyrrolidinone and heating in a 150 W microwave at up to 150° C.for 5 min. Nitrile compounds of formula (II) may also be formed from thecorresponding halo compound of formula (II) from the reaction of asuitable cyanide source such as potassium hexacyanoferrate, atransmetallating agent such as copper iodide, a salt such as potassiumiodide, and a coordinating agent such as dimethylethylenediamine in apolar solvent such as N-methylpyrrolidinone under an inert atmosphere atelevated temperatures up to 140° C. for up to 60 hours.

Compounds of formula (II) may be prepared from compounds of formula(III) by standard dehydration conditions, optionally R⁶ may be asuitable protecting group e.g. benzyl, or substituted benzyl.

Thus, dehydration may be effected under acidic conditions. For examplecompounds of formula (III) may be treated with an inorganic acid such ashydrochloric acid (4-6N) or concentrated sulphuric acid, for up to 72 h,optionally in an organic miscible solvent such as acetonitrile,optionally at elevated temperatures up to 60° C. Alternatively,dehydration may result from heating compounds of formula (III) at refluxwith an organic acid such as trifluoroacetic acid or p-toluenesulphonicacid in an aprotic solvent such as toluene. Otherwise, compounds offormula (III) may be dehydrated using Eaton's reagent, typicallystirring at room temperature for several hours neat or in a polarsolvent such as methanol. Dehydration may also be effected by treating acompound of formula (III) with thionyl chloride in a polar solvent suchas acetonitrile.

Compounds of formula (III) may be used to directly access compounds offormula (I) upon treatment with Pearlman's catalyst in a suitable proticsolvent such as methanol under a hydrogen atmosphere, in cases whereinR⁶ is a benzylic protecting group a deprotected compound of formula (I)will be obtained wherein R⁶ is hydrogen. Alternatively, compounds offormula (III) wherein R⁶ is a protecting group such as benzyl may bedeprotected, dehydrated and reduced simultaneously by hydrogenationunder acidic conditions. For example, upon treatment of compounds offormula (III) with a hydrogen source such as ammonium formate in thepresence of an acid such as formic acid and 10% palladium on carbon,optionally for up to 72 h, compounds of formula (I) wherein R⁶ ishydrogen are obtained.

Compounds of formula (II) may be obtained by dehydrohalogenationprocedures, known to the skilled man, from compounds of formula (III)for example by standard chlorination followed by dehydrochlorinationprocedures.

Alternatively, compounds of formula (II) can be obtained by transitionmetal catalysed cross-coupling reactions by utilizing methods known inthe literature. For these reactions, it may be necessary to protect thebasic imidazole, optionally R⁶ may include a suitable protecting groupsuch as diethoxymethyl. Thus, suitably protected organozincates such ascompounds of formula (V), wherein X is halo for example chloro or bromo,can be coupled with suitably substituted styrenes such as compounds offormula (IV) wherein Y is a group suitable for transmetallation such asOTf, Cl, Br or I in the presence of a palladium catalyst such asPd(PPh₃)₃.

Standard deprotection of compounds of formula (II) wherein R⁶ is asuitable protecting group provides compounds of formula (II) in which R⁶is hydrogen. For example, when R⁶ is diethoxymethyl treatment with anorganic acid such as trifluoroacetic acid or an inorganic acid such ashydrochloric acid provides compound (II) wherein R⁶ is hydrogen.Similarly, deprotection of compounds of formula (II) wherein R⁶ is abenzyl moiety protecting group may easily be effected by hydrogenation.

Compounds of formula (III) wherein R⁶ is a protecting group can beformed by 1,2-addition of a suitably protected organometallic compound(VI) to the corresponding ketone (VII) where chemically feasible forexample wherein R¹, R², R³, R⁴ and R⁵ may be chosen independently fromalkyl, chloro, and R^(a) and R^(b) may be chosen from alkyl.

For example, compound (VI) may be reacted with ketone (VII) in anaprotic solvent such as tetrahydrofuran at temperatures typicallyranging from −80 to 0° C. to give compounds of formula (III), which canbe readily deprotected to give a compound of formula (III) wherein R⁶ isH if desired.

Alternative organometallic chemistry may be utilized to yield a compoundof formula (III), wherein R⁶ is a suitable protecting group such asbenzyl, when an organometallic compound of formula (VIII), wherein X maybe a halo e.g. chloro or bromo, is added to a ketone of formula (IX)wherein R⁶ is a protecting group.

Similarly, compounds of formula (III) wherein R⁶ is optionally asuitable protecting group such as benzyl may also be accessed byorganometallic addition to a protected ketone (X), suitableorganometallic reagents include Grignard reagents and organolithiumreagents. For example, a Grignard reagent such as methylmagnesiumchloride may be added to a solution of compound (X) in an anhydrous,aprotic solvent such as tetrahydrofuran, toluene or diethyl ether at−10°-0° C. for up to 4 h to provide compounds of formula (III) whereinR^(a) and R^(b) are H.

Compounds of formula (III) wherein R⁶ is a protecting group such asbenzyl may be deprotected using standard hydrogenation conditions suchas 10% palladium on carbon in a protic solvent at elevated pressure andtemperature to give deprotected compounds of formula (III) wherein R⁶ ishydrogen. Deprotecting compounds of formula (III) in a stepwise manner,before dehydration to produce compounds of formula (II), allowscompounds of formula (II) to be stereoselectively reduced to givecompounds of formula (I) if desired.

Compounds of formula (IV), (V), (VI), (VII), (VIII), and (IX) mayreadily be accessed by utilisation of literature methods or simplemodifications thereof as would be routinely employed by a skilled man.For example, compounds of formula (V) can be prepared by stirring a1-protected imidazole with n-butyllithium at reduced temperature,typically −60 to −20° C. followed by the addition of zinc chloride andallowing to warm to room temperature.

For example, compound (VI) may be obtained in situ by treatment of aprotected imidazole reactant, with an organolithium reagent such asn-butylithium in an aprotic solvent such as tetrahydrofuran at reducedtemperatures typically ranging from −80 to 0° C. Suitable protectinggroups include diethoxymethyl.

For example, compounds of formula (IX) may be synthesised by acylating asuitably substituted imidazole using acid chlorides. Thus, heating forseveral hours a suitable acid chloride with a 1-protected imidazole inthe presence of a mild base such as triethylamine provides compounds offormula (IX).

Compounds of formula (VII) may be accessed in a number of ways. Somemethods utilise simple precursors as detailed below.

Compounds of formula (VII) may be prepared by the addition of achelating agent such as Fe(acac)₃ and a Grignard reagent such asmethylmagnesium bromide to a suitably substituted acid chloride (XI) atreduced temperatures, typically −20° C. in a suitable aprotic solvent.Acid chlorides (XI) may be prepared by the reaction of the correspondingbenzoic acid (XII) with thionyl chloride or oxalyl chloride, at elevatedtemperatures, typically 100° C. for several hours.

Compounds of formula (VII) may also be prepared by reaction of an acidanhydride such as acetic anhydride, with a phenyl Grignard reactant(XIII) in an aprotic solvent. Alternatively, amides, or acid chloridesmay be used in place of the acid anhydride. Compounds of formula (XIII)may be formed in situ by reacting a suitable bromobenzene derivativewith magnesium turnings in an anhydrous, aprotic solvent such astetrahydrofuran.

Similarly, compounds of formula (VII) may be prepared by reacting aGrignard reactant e.g. methylmagnesium bromide with an amide e.g. asuitably substituted benzoylmorpholine (XIV) at reflux in a suitablesolvent such as tetrahydrofuran.

Compounds of formula (VII) may also be obtained from reaction of asuitable benzoic acid (XII) with an organolithium reactant, for examplemethyllithium, at reduced temperatures in an anhydrous aprotic solventsuch as tetrahydrofuran.

Compounds of formula (VII) may be obtained by Friedel Crafts acylationof suitably functionalized phenyl moieties. For example, afunctionalized phenyl reactant can be treated with a Lewis acid such asaluminium chloride, in the presence of a suitable acylating agent suchas acetyl chloride, in an aprotic solvent such as dichloromethane atroom temperature for up to 18 h to give the desired compounds of formula(VI).

Alternatively compounds of formula (VII) may by obtained in a two stepprocedure from a suitably substituted halobenzene, preferably bromo oriodo benzene. For example a bromobenzene compound may be transmetallatedwith an organometallic reagent such as n-butyllithium in an anhydrous,apolar solvent such as tetrahydrofuran at low temperatures down to −80°C. followed by electrophilic quenching with an aldehyde to give thecorresponding secondary alcohol which may be oxidized under standardconditions, for example using Dess Martin periodinane, to give compoundsof formula (VII) wherein R^(a) is selected from H, C₁₋₄alkyl, orC₀₋₄alkylenephenyl and R^(b)=C₁₋₄alkyl, or C₀₋₄alkylenephenyl.

Compounds of formula (VII) may also be formed from the correspondingaryliodide and boronic acids using palladium chemistry in a carbonmonoxide atmosphere. Thus, heating aryliodides with carbon monoxide,methylboronic acid and palladium tetrakis triphenylphosphine providescompounds of formula (VII) wherein R^(a) and R^(b) are H.

Compounds of formula (VII) may undergo standard chemical reactions andfunctional group interonversion reactions known to the skilled man togive other compounds of formula (VII). Thus, compounds of formula (VII)may be chlorinated using standard reagents such as Selectafluor™ andsodium chloride. Also, suitably substituted halo compounds of formula(VII) may undergo standard palladium catalysed cross coupling reactionssuch as Suzuki, Stille, Heck reactions to give a variety of standardproducts. For example, bromo or iodo compounds of formula (VII) mayundergo alkylation and arylation reactions via Suzuki coupling reactionsupon treatment with an organoborane e.g. triethyl borane in the presenceof [1,1-bis(diphenylphosphino)ferocene]palladium (II) chloride, andpotassium carbonate in an aprotic solvent such as N,N-dimethylformamideto give alkyl or aryl substituted compounds of formula (VII).

Compounds of formula (X) may be obtained from the reaction of acidchlorides of formula (XI) and imidazoles of formula (XV) wherein R⁶ is asuitable protecting group in a suitable aprotic solvent such as tolueneor acetonitrile in the presence of a mild base such as triethylamine attemperatures ranging from −10°-130° C.

Suitably functionalised acid chlorides of formula (XI) may besynthesized from the corresponding acid upon treatment with thionylchloride at 80° C. for ˜1 hour. Alternatively, acid chlorides may besynthesized from carboxylic acids upon treatment with oxalyl chloride inan aprotic solvent such as toluene at room temperature for up to 4hours. Suitably functionalized acids may be obtained by utilisingstandard literature procedures available to the skilled man, thussubstituents may be introduced via electrophilic or nucleophilicsubstitution or cross coupling reactions or via functional groupinterconversion.

Compounds of formula (X) can also be synthesized by oxidation ofcompounds of formula (XVI) by suitable oxidising agents, wherein R⁶ ishydrogen or a suitable protecting group.

One such oxidation may include Dess Martin oxidation conditions. Forexample, a compound of formula (X), may be prepared by stirring thecorresponding compound of formula (XVI) at room temperature withDess-Martin Periodinane in a suitable polar solvent such asdichloromethane.

Compounds of formula (XVI) may be formed by the 1,2-addition of asuitably protected organometallic compound to a suitable aldehyde. Thusreaction of an organolithium compound of formula (VI) and acorresponding aldehyde of formula (XVII), in an anhydrous, aproticsolvent such as tetrahydrofuran at temperatures ranging from −80-0° C.provides compounds of formula (XVI).

It is to be understood that precursors to compounds of formula (I) andcompounds of formula (I) themselves may undergo functional groupinterconversion in order to deliver alternative compounds of formula(I). For example compounds of formula (I) wherein R⁶ is hydrogen may bereacted with alkylating agents of the formula L-C₀₋₂alkyleneR⁷,L-C₁₋₂alkyleneOR⁷, L-C₁₋₂alkyleneC(O)R⁷, L-C₁₋₂alkyleneOC(O)R⁷,L-C₁₋₂alkyleneOC(O)OR⁷, L-C₁₋₂alkyleneC(O)OR⁷, L-C₁₋₂alkyleneN(H)C(O)R⁷,L-C₁₋₂alkyleneN(R⁷)C(O)R⁷, L-C₁₋₂alkyleneC(O)NHR⁷,L-C₁₋₂alkyleneNHC(O)NR¹⁵R¹⁶, L-C₁₋₂alkyleneNR⁷C(O)NR¹⁵R¹⁶,L-C₁₋₂alkyleneC(O)NR¹⁵R¹⁶, L-C₁₋₂alkyleneOC(O)NHR⁷,L-C₁₋₂alkyleneOC(O)NR¹⁵R¹⁶, to provide compounds wherein R⁶ is—C₀₋₂alkyleneR⁷, —C₁₋₂alkyleneOR⁷, —C₁₋₂alkyleneC(O)R⁷,—C₁₋₂alkyleneOC(O)R⁷, —C₁₋₂alkyleneOC(O)OR⁷, —C₁₋₂alkyleneC(O)OR⁷,—C₁₋₂alkyleneN(H)C(O)R⁷, —C₁₋₂alkyleneN(R⁷)C(O)R⁷, C₁₋₂alkyleneC(O)NHR⁷,—C₁₋₂alkyleneNHC(O)NR¹⁵R¹⁶, —C₁₋₂alkyleneNR⁷C(O)NR¹⁵R¹⁶,—C₁₋₂alkyleneC(O)NR¹⁵R¹⁶, —C₁₋₂alkyleneOC(O)NHR⁷,—C₁₋₂alkyleneOC(O)NR¹⁵R¹⁶. L is a suitable leaving group such as Cl, Br,I, or a sulfonate such as trifluoromethanesulfonate. For examplecompounds of formula (I) wherein R⁶ is hydrogen may be reacted withalkylating agents in the presence of a mild base such as cesiumcarbonate, potassium carbonate, triethylamine, or diisopropylethylamine,in an aprotic solvent such as acetone, 1-methyl-2-pyrrolidinone,dichloromethane, tetrahydrofuran, acetonitrile or N,N-dimethylformamideoptionally in the presence of a salt such as sodium iodide. Generallythe alkylation reaction will proceed for up to 72 h at room temperature,optionally the reaction may be heated to reflux or may be microwaved at200 W for up to 1 h.

Alkylating agents of the form Cl—CH₂OC(O)R⁷ may be produced from thereaction of the acid chloride ClC(O)R⁷ with paraformaldehyde in thepresence of a Lewis acid such as zinc chloride at temperatures up to 80°C. for 2-3 hours. Under alkylating conditions such reagents givecompounds of formula (I) wherein R⁶ is CH₂OC(O)R⁷.

Alkylating agents of the form L-CH₂OC(O)OR⁷ may be produced from thereaction of the alcohol HOR⁷ with chloromethyl chloroformate in anaprotic solvent such as dichloromethane at temperatures ranging from 0°C. to room temperature. Under alkylating conditions such reagents givecompounds of formula (I) wherein R⁶ is CH₂OC(O)OR⁷.

Alkylating agents of the form L-CH₂OC(O)NHR⁷ may be produced from thereaction of the amine R⁷NH₂ with chloromethyl chloroformate in anaprotic solvent such as dichloromethane at temperatures ranging from−10° C. to room temperature. Under alkylating conditions such reagentsgive compounds of formula (I) wherein R⁶ is CH₂OC(O)NHR⁷.

Alkylating agents of the form L-CH₂OC(O)NR¹⁵R¹⁶ may be produced from thereaction of the amine R¹⁵R¹⁶NH with chloromethyl chloroformate in anaprotic solvent such as dichloromethane optionally in the presence of amild base such as diisopropylethylamine at temperatures ranging from −0°C. to room temperature. Under alkylating conditions such reagents givecompounds of formula (I) wherein R⁶ is CH₂OC(O)NR¹⁵R¹⁶.

Compounds of formula (I) wherein R⁵ is hydrogen may be reacted withacylating agents of the formula ClC(O)R⁷, O[OC(O)R⁷]₂, ClC(O)OR⁷,ClC(O)NHR⁷, ClC(O)NR¹⁵R¹⁶, to provide compounds wherein R⁶ is —C(O)R⁷,—OC(O)R⁷, —C(O)OR⁷, —C(O)NHR⁷, —C(O)NR¹⁵R¹⁶. For example compounds offormula (I) wherein R⁶ is hydrogen may be reacted with acylating agentsin the presence of a mild base such as triethylamine, or pyridine in anaprotic solvent such as dichloromethane, tetrahydrofuran or acetonitrileat temperatures ranging from room temperature to 100° C. for between 1and 36 h.

It is possible to form the acylating agent ClC(O)OR⁷ in situ. Thus acompound of formula (I) wherein R⁶ is hydrogen, may be reacted withphosgene or diphosgene in an anhydrous solvent such as dichloromethaneor acetonitrile in the presence of a mild base such as pyridine in thepresence of an alcohol R⁷OH at ambient temperature to give the compoundof formula (I) wherein R⁶ is C(O)OR⁷.

Compounds of formula (I) wherein R⁶ is hydrogen may be reacted withphosphorylating agents of the formula Cl—P(═O)[N(R⁷)₂(R⁷)₂] to givecompounds of formula (I) wherein R⁶ is P(═O)[N(R⁷)₂(R⁷)₂]. For examplereaction with a corresponding bis(dialkylamino)phosphoryl chloride e.g.bis(dimethylamino)phosphoryl chloride in an aprotic solvent such asdichloromethane.

Compounds of formula (I) wherein R⁶ is hydrogen may be reacted withsilating agents of the formula Cl—Si(R⁷) to give compounds of formula(I) wherein R⁶ is Si(R⁷)₃ For example reaction with a correspondingalkylsilane or arylsilane e.g. chlorotrimethylsilane in an aproticsolvent such as dichloromethane or tetrahydrofuran.

Compounds of formula (I) wherein R⁶ is hydrogen may be reacted withsulphonating agents of the formula Cl—S(═O)₂R¹⁰ to give compounds offormula (I) wherein R⁶ is S(═O)₂R¹⁰. For example reaction with acorresponding sulphonyl chloride e.g. methanesulphonyl chloride in anaprotic solvent such as dichloromethane, optionally with a weak basesuch as triethylamine.

Compounds of formula (I) wherein R⁶ is hydrogen may be reacted withcyanogen bromide in an aprotic solvent such as dichloromethane,optionally with a weak base such as diisopropylethylamine to givecompounds of formula (I) wherein R⁶ is CN.

Compounds of formula (III) may be alkylated to give compounds of formula(I) wherein R⁹ is C₁-C₄ alkoxy. Thus, treatment of compounds of formula(III) with a strong base such as sodium hydride in an aprotic solventsuch as tetrahydrofuran followed by addition of an alkylating agent willprovide compounds of formula (I) wherein R⁹ is C₁-C₄ alkoxy.

Compounds of formula (II) may be cyclopropanated to give compounds offormula (I) wherein R⁸ and R⁹ together form a cyclopropyl ring.Compounds of formula (II) may be reacted with a carbenoid species,CR^(d)R^(e). For example, when R^(d)=R^(e)=F, a reactive species such astrimethylsilyl difluoro(fluorosulfonyl)acetate (TFDA) may be reactedwith a compound of formula (II), with an optional apolar solvent atelevated temperature in the presence of sodium fluoride to yield aproduct of formula (I) after deprotection, wherein the cyclopropyl ringis substituted with fluoro.

Other specific methods include treatment of chloroform with base,preferably under phase transfer catalysis conditions, thermolysis of asuitable organometallic precursor such as an aryl trifluoromethyl,trichloromethyl, or phenyl(trifluoromethyl) mercury derivative ortreatment with a diazoalkane in the presence of a transition metalcatalyst and treatment with a diazoalkane in the absence of a transitionmetal catalyst followed by thermolysis of the intermediate pyrazoline,or generation from a sulphur ylid.

Moreover, persons skilled in the art will be aware of variations of, andalternatives to, the processes described which allow the compoundsdefined by formula (I) to be obtained.

It will also be appreciated by persons skilled in the art that, withincertain of the processes described, the order of the synthetic stepsemployed may be varied and will depend inter alia on factors such as thenature of other functional groups present in a particular substrate, theavailability of key intermediates, and the protecting group strategy (ifany) to be adopted. Clearly, such factors will also influence the choiceof reagent for use in the said synthetic steps.

The skilled person will appreciate that the compounds of the inventioncould be made by methods other than those herein described, byadaptation of the methods herein described and/or adaptation of methodsknown in the art, for example the art described herein, or usingstandard textbooks such as “Comprehensive Organic Transformations—AGuide to Functional Group Transformations”, R C Larock, Wiley-VCH (1999or later editions).

It is to be understood that the synthetic transformation methodsmentioned herein are exemplary only and they may be carried out invarious different sequences in order that the desired compounds can beefficiently assembled. The skilled chemist will exercise his judgementand skill as to the most efficient sequence of reactions for synthesisof a given target compound.

Further examples of replacement groups in accordance with the foregoingexamples and examples of other prodrug types may be found in theaforementioned references.

The present invention also relates to intermediates of formula (LX)below:

where:

-   R¹-R¹², R^(a), R^(b), and n are all as defined for formula (I) above    or a pharmaceutical salt or a prodrug thereof. With reference to    formula (LX), suitably R¹ and R² are selected from C₁₋₄ alkyl and    R³, R⁴ and R⁵ are hydrogen.

The present invention also relates to intermediates of formula (LXV)below:

where:

-   R¹-R¹², R^(a), R^(b), and n are all as defined for formula (I) above    and where Pg is a chemical protecting group or a pharmaceutical salt    or a prodrug thereof. With reference to formula (LXV), suitably R¹    and R² are selected from C₁₋₄ alkyl and R³, R⁴ and R⁵ are hydrogen.

The present invention also relates to intermediates of formula (LXX)below:

where:

-   R¹-R¹², R^(a), R^(b), and n are all as defined for formula (I) above    and where Pg is a chemical protecting group or a pharmaceutical salt    or a prodrug thereof. With reference to formula (LXX), suitably R¹    and R² are selected from C₁₋₄ alkyl and R³, R⁴ and R⁵ are hydrogen.

It will be understood that throughout the application all references toformula (I) apply equally to compounds of the formulas (LX), (LXV) and(LXX) above.

Furthermore, it will be understood that all the suitable groups andpreferences applied to R¹-R¹², R^(a), R^(b), and n for formula (I) applyequally to compounds of the formulas (LX), (LXV) and (LXX) above.

Finally, certain compounds of formula (I) may themselves act asintermediates in the preparation of other compounds of formula (I).

One of ordinary skill in the art would understand that Pg in theformulas (LX), (LXV) and (LXX) above can represent a wide range ofpossible protecting group and the specific group required will depend onthe final compounds to be made and can be readily selected by one ofordinary skill. Preferred protecting groups include benzyl,para-methoxybenzyl, allyl, trityl, or 1,1-diethoxymethyl, preferablybenzyl.

This invention also relates to a pharmaceutical composition comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,or a pharmaceutically acceptable solvate of either entity, together witha pharmaceutically acceptable diluent or carrier, which may be adaptedfor oral, parenteral or topical administration.

Pharmaceutical compositions suitable for the delivery of compounds ofthe present invention and methods for their preparation will be readilyapparent to those skilled in the art. Such compositions and methods fortheir preparation may be found, for example, in ‘Remington'sPharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).

Compounds of the invention intended for pharmaceutical use may beadministered as crystalline or amorphous products. They may be obtained,for example, as solid plugs, powders, or films by methods such asprecipitation, crystallization, freeze drying, or spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose.

The methods by which the compounds may be administered include oraladministration by capsule, bolus, tablet, powders, lozenges, chews,multi and nanoparticulates, gels, solid solution, films, sprays, orliquid formulation. Liquid forms include suspensions, solutions, syrups,drenches and elixirs. Such formulations may be employed as fillers insoft or hard capsules and typically comprise a carrier, for example,water, ethanol, polyethylene glycol, propylene glycol, methylcellulose,or a suitable oil, and one or more emulsifying agents and/or suspendingagents. Liquid formulations may also be prepared by the reconstitutionof a solid, for example, from a sachet. Oral drenches are commonlyprepared by dissolving or suspending the active ingredient in a suitablemedium.

Compounds of the present invention may be administered alone or incombination with one or more other compounds of the invention or incombination with one or more other drugs (or as any combinationthereof). The compounds may be administered alone or in a formulationappropriate to the specific use envisaged, the particular species ofhost mammal being treated and the parasite involved. Generally, theywill be administered as a formulation in association with one or morepharmaceutically acceptable excipients. The term “excipient” is usedherein to describe any ingredient other than the compound(s) of theinvention. The choice of excipient will to a large extent depend onfactors such as the particular mode of administration, the effect of theexcipient on solubility and stability, and the nature of the dosageform.

Thus compositions useful for oral administration may be prepared bymixing the active ingredient with a suitable finely divided diluentand/or disintegrating agent and/or binder, and/or lubricant etc. Otherpossible ingredients include anti-oxidants, colourants, flavouringagents, preservatives and taste-masking agents.

For oral dosage forms, depending on dose, the drug may make up from 1 wt% to 80 wt % of the dosage form, more typically from 5 wt % to 60 wt %of the dosage form. Examples of disintegrants include sodium starchglycolate, sodium carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone,methyl cellulose, microcrystalline cellulose, lower alkyl-substitutedhydroxypropyl cellulose, starch, pregelatinised starch and sodiumalginate. Generally, the disintegrant will comprise from 1 wt % to 25 wt%, preferably from 5 wt % to 20 wt % of the dosage form.

Binders are generally used to impart cohesive qualities to a tabletformulation. Suitable binders include microcrystalline cellulose,gelatin, sugars, polyethylene glycol, natural and synthetic gums,polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose andhydroxypropyl methylcellulose. Examples of diluents include lactose(monohydrate, spray-dried monohydrate, anhydrous and the like),mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystallinecellulose, starch and dibasic calcium phosphate dihydrate.

Oral formulations may also optionally comprise surface active agents,such as sodium lauryl sulfate and polysorbate 80, and glidants such assilicon dioxide and talc. When present, surface active agents maycomprise from 0.2 wt % to 5 wt % of the tablet, and glidants maycomprise from 0.2 wt % to 1 wt % of the tablet.

Lubricants include magnesium stearate, calcium stearate, zinc stearate,sodium stearyl fumarate, and mixtures of magnesium stearate with sodiumlauryl sulphate. Lubricants generally comprise from 0.25 wt % to 10 wt%, preferably from 0.5 wt % to 3 wt % of the tablet.

Exemplary tablets contain up to about 80% drug, from about 10 wt % toabout 90 wt % binder, from about 0 wt % to about 85 wt % diluent, fromabout 2 wt % to about 10 wt % disintegrant, and from about 0.25 wt % toabout 10 wt % lubricant.

The formulation of tablets is discussed in “Pharmaceutical Dosage Forms:Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y.,1980 (ISBN 0-8247-6918-X).

The compounds may be administered topically to the skin or mucosa, thatis dermally or transdermally. This is a preferred method ofadministration and as such it is desirable to develop active compounds,which are particularly suited to such formulations. Typical formulationsfor this purpose include pour-on, spot-on, dip, spray, mousse, shampoo,powder formulation, gels, hydrogels, lotions, solutions, creams,ointments, dusting powders, dressings, foams, films, skin patches,wafers, implants, sponges, fibres, bandages and microemulsions.Liposomes may also be used. Typical carriers include alcohol, water,mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethyleneglycol and propylene glycol. Penetration enhancers may beincorporated—see, for example, J Pharm Sci, 88 (10), 955-958 by Finninand Morgan (October 1999). Pour-on or spot-on formulations may beprepared by dissolving the active ingredient in an acceptable liquidcarrier vehicle such as butyl digol, liquid paraffin or a non-volatileester, optionally with the addition of a volatile component such aspropan-2-ol. Alternatively, pour-on, spot-on or spray formulations canbe prepared by encapsulation, to leave a residue of active agent on thesurface of the animal, this effect may ensure that the compounds offormula (I) have increased persistence of action and are more durable,for example they may be more waterfast.

Agents may be added to the formulations of the present invention toimprove the persistence of such formulations on the surface of theanimal to which they are applied, for example to improve theirpersistence on the coat of the animal. It is particularly preferred toinclude such agents in a formulation which is to be applied as a pour-onor spot-on formulation. Examples of such agents acrylic copolymers andin particular fluorinated acrylic copolymers. A particular suitablereagent is Foraperle (Redline Products Inc, Texas, USA).

Certain topical formulations may include unpalatable additives tominimize accidental oral exposure.

Injectable formulations may be prepared in the form of a sterilesolution, which may contain other substances, for example enough saltsor glucose to make the solution isotonic with blood. Acceptable liquidcarriers include vegetable oils such as sesame oil, glycerides such astriacetin, esters such as benzyl benzoate, isopropyl myristate and fattyacid derivatives of propylene glycol, as well as organic solvents suchas pyrrolidin-2-one and glycerol formal. The formulations are preparedby dissolving or suspending the active ingredient in the liquid carriersuch that the final formulation contains from 0.01 to 10% by weight ofthe active ingredient.

Alternatively, the compounds can be administered parenterally, or byinjection directly into the blood stream, muscle or into an internalorgan. Suitable means for parenteral administration include intravenous,intraarterial, intraperitoneal, intrathecal, intraventricular,intraurethral, intrasternal, intracranial, intramuscular andsubcutaneous. Suitable devices for parenteral administration includeneedle (including microneedle) injectors, needle-free injectors andinfusion techniques. Parenteral formulations are typically aqueoussolutions which may contain excipients such as salts, carbohydrates andbuffering agents (preferably to a pH of from 3 to 9), but, for someapplications, they may be more suitably formulated as a sterilenon-aqueous solution or as powdered a dried form to be used inconjunction with a suitable vehicle such as sterile, pyrogen-free water.The preparation of parenteral formulations under sterile conditions, forexample, by lyophilisation, may readily be accomplished using standardpharmaceutical techniques well known to those skilled in the art. Thesolubility of compounds of formula (I) used in the preparation ofparenteral solutions may be increased by the use of appropriateformulation techniques, such as the incorporation ofsolubility-enhancing agents.

Such formulations are prepared in a conventional manner in accordancewith standard medicinal or veterinary practice.

These formulations will vary with regard to the weight of activecompound contained therein, depending on the species of host animal tobe treated, the severity and type of infection and the body weight ofthe host. For parenteral, topical and oral administration, typical doseranges of the active ingredient are 0.01 to 100 mg per kg of body weightof the animal. Preferably the range is 0.1 to 10 mg per kg.

Formulations may be immediate and/or modified controlled release.Controlled release formulations include modified release formulationsincluding delayed-, sustained-, pulsed-, controlled, targeted, orprogrammed release. Suitable modified release formulations for thepurposes of the invention are described in U.S. Pat. No. 6,106,864.Details of other suitable release technologies such as high energydispersions and osmotic and coated particles are to be found in Verma etal, Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use ofchewing gum to achieve controlled release is described in WO 00/35298.Alternatively, compounds of the invention may be formulated as a solid,semi-solid, or thixotropic liquid for administration as an implanteddepot providing modified release of the active compound. Examples ofsuch formulations include drug-coated stents and PGLA microspheres.

As an alternative the compounds may be administered to a non-humananimal with the feedstuff and for this purpose a concentrated feedadditive or premix may be prepared for mixing with the normal animalfeed.

All the aforementioned aqueous dispersions or emulsions or sprayingmixtures can be applied, for example, to crops by any suitable means,chiefly by spraying, at rates which are generally of the order of about100 to about 1,200 liters of spraying mixture per hectare, but may behigher or lower (eg. low or ultra-low volume) depending upon the need orapplication technique. The compounds or compositions according to theinvention are conveniently applied to vegetation and in particular toroots or leaves having pests to be eliminated. Another method ofapplication of the compounds or compositions according to the inventionis by chemigation, that is to say, the addition of a formulationcontaining the active ingredient to irrigation water. This irrigationmay be sprinkler irrigation for foliar pesticides or it can be groundirrigation or underground irrigation for soil or for systemicpesticides.

The concentrated suspensions, which can for example be applied byspraying, are prepared so as to produce a stable fluid product whichdoes not settle (fine grinding) and usually contain from about 10 toabout 75% by weight of active ingredient, from about 0.5 to about 30% ofsurface-active agents, from about 0.1 to about 10% of thixotropicagents, from about 0 to about 30% of suitable additives, such asanti-foaming agents, corrosion inhibitors, stabilizers, penetratingagents, adhesives and, as the carrier, water or an organic liquid inwhich the active ingredient is poorly soluble or insoluble. Some organicsolids or inorganic salts may be dissolved in the carrier to helpprevent settling or as antifreezes for water.

The wettable powers (or powder for spraying) are usually prepared sothat they contain from about 10 to about 80% by weight of activeingredient, from about 20 to about 90% of a solid carrier, from about 0to about 5% of a wetting agent, from about 3 to about 10% of adispersing agent and, when necessary, from about 0 to about 80% of oneor more stabilizers and/or other additives, such as penetrating agents,adhesives, anti-caking agents, colorants, or the like. To obtain thesewettable powders, the active ingredient(s) is(are) thoroughly mixed in asuitable blender with additional substances which may be impregnated onthe porous filler and is(are) ground using a mill or other suitablegrinder. This produces wettable powders, the wettability and thesuspendability of which are advantageous. They may be suspended in waterto give any desired concentration and this suspension can be employedvery advantageously in particular for application to plant foliage.

The “water dispersible granules (WG)” (granules which are readilydispersible in water) have compositions which are substantially close tothat of the wettable powders. They may be prepared by granulation offormulations described for the wettable powders, either by a wet route(contacting finely divided active ingredient with the inert filler and alittle water, e.g. 1 to 20% by weight, or with an aqueous solution of adispersing agent or binder, followed by drying and screening), or by adry route (compacting followed by grinding and screening).

Depending on the method of application or the nature of the compositionor use thereof, the rates and concentrations of the formulatedcompositions may vary according. Generally speaking, the compositionsfor application to control arthropod, plant nematode, helminth orprotozoan pests usually contain from about 0.00001% to about 95%, moreparticularly from about 0.0005% to about 50% by weight of one or morecompounds of formula (I), or pesticidally acceptable salts thereof, orof total active ingredients (that is to say the compound of formula (I),or a pesticidally acceptable salt thereof, together with: othersubstances toxic to arthropods or plant nematodes, anthelmintics,anticoccidials, synergists, trace elements or stabilizers). The actualcompositions employed and their rate of application will be selected toachieve the desired effect(s) by the farmer, livestock producer, medicalor veterinary practitioner, pest control operator or other personskilled in the art.

The compounds of the invention may be combined with solublemacromolecular entities, such as cyclodextrin and suitable derivativesthereof or polyethylene glycol-containing polymers, in order to improvetheir solubility, dissolution rate, taste-masking, bioavailabilityand/or stability for use in any of the aforementioned modes ofadministration.

Drug-cyclodextrin complexes, for example, are found to be generallyuseful for most dosage forms and administration routes. Both inclusionand non-inclusion complexes may be used. As an alternative to directcomplexation with the drug, the cyclodextrin may be used as an auxiliaryadditive, i.e. as a carrier, diluent, or solubiliser. Most commonly usedfor these purposes are alpha-, beta- and gamma-cyclodextrins, examplesof which may be found in International Patent Applications Nos. WO91/11172, WO 94/02518 and WO 98/55148.

Compounds of the invention can also be mixed with one or morebiologically active compounds or agents including insecticides,acaricides, anthelmintics, fungicides, nematocides, antiprotozoals,bactericides, growth regulators, entomopathogenic bacteria, viruses orfungi to form a multi-component pesticide giving an even broaderspectrum of pharmaceutical, veterinary or agricultural utility. Thus,the present invention also pertains to a composition comprising abiologically effective amount of compounds of the invention and aneffective amount of at least one additional biologically active compoundor agent and can further comprise one or more of surfactant, a soliddiluent or a liquid diluent. Specific further active compounds includethose described in International Patent Application No WO0 2005/090313,at pages 39 to 44.

It be may desirable to administer a combination of active compounds, forexample, for the purpose of treating a particular disease or condition,it is within the scope of the present invention that two or morepharmaceutical compositions, at least one of which contains a compoundin accordance with the invention, may conveniently be combined in theform of a kit suitable for coadministration of the compositions.

Thus the kit of the invention comprises two or more separatepharmaceutical compositions, at least one of which contains a compoundof formula (I) in accordance with the invention, and means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is the familiarblister pack used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administeringdifferent dosage forms, for example, oral and parenteral, foradministering the separate compositions at different dosage intervals,or for titrating the separate compositions against one another. Toassist compliance, the kit typically comprises directions foradministration and may be provided with a so-called memory aid.

The compounds of the invention, i.e. those of formula (I), possessparasiticidal activity in humans, animals, insects and plants. They areparticularly useful in the treatment of ectoparasites.

This invention also relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of either entity, or a pharmaceutical compositioncontaining any of the foregoing, for use as a medicament.

A further aspect of this invention relates to the use of a compound offormula (I), or a pharmaceutically acceptable salt thereof, or apharmaceutically acceptable solvate of either entity, for themanufacture of a medicament for the treatment of a parasiticinfestation.

In one embodiment this invention is useful for the manufacture of amedicament for the treatment of a parasitic infestation in humans.

In one embodiment this invention is useful for the manufacture of amedicament for the treatment of a parasitic infestation in animals.

In one embodiment this invention is useful for the manufacture of amedicament for the treatment of a parasitic infestation in insects.

In one embodiment this invention is useful for the manufacture of amedicament for the treatment of a parasitic infestation in plants.

An even further aspect of this invention relates to a method of treatinga parasitic infestation in a mammal which comprises treating said mammalwith an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of either entity, or a pharmaceutical compositioncontaining any of the foregoing.

A yet further aspect of this invention relates to a method of preventinga parasitic infestation in a mammal which comprises treating said mammalwith an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of either entity, or a pharmaceutical compositioncontaining any of the foregoing.

In a still further embodiment this invention also relates to a method ofcontrolling disease transmission in a mammal which comprises treatingsaid mammal with an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable solvate of either entity, or a pharmaceutical compositioncontaining any of the foregoing.

According to another aspect of the present invention, there is provideda method for the control of arthropod, plant nematode or helminth pestsat a locus which comprises the treatment of the locus (e.g. byapplication or administration) with an effective amount of a compound ofgeneral formula (I), or a pesticidally acceptable salt thereof.

For the avoidance of doubt, references herein to “treatment” as usedherein includes references to curative, palliative and prophylactictreatment, references to “control” (of parasites and/or pests etc.)include kill, repel, expel, incapacitate, deter, eliminate, alleviate,minimise, eradicate.

The compounds of the invention have utility in the control of arthropodpests. They may, in particular, be used in the fields of veterinarymedicine, livestock husbandry and the maintenance of public health:against arthropods which are parasitic internally or externally uponvertebrates, particularly warm-blooded vertebrates, including man anddomestic animals such as dogs, cats, cattle, sheep, goats, equines,swine, poultry and fish for example Acarina, including ticks (e.g.Ixodes spp., Boophilus spp. e.g. Boophilus microplus, Amblyomma spp.,Hyalomma spp., Rhipicephalus spp. e.g. Rhipicephalus appendiculatus,Haemaphysalis spp., Dermacentor spp., Ornithodorus spp. (e.g.Ornithodorus moubata), mites (e.g. Damalinia spp., Dermanyssus gallinae,Sarcoptes spp. e.g. Sarcoptes scabiei, Psoroptes spp., Chorioptes spp.,Demodex spp., Eutrombicula spp.), specific further arthropod pestsinclude those described in International Patent Application No WO2005/090313; Diptera (e.g. Aedes spp., Anopheles spp., Muscidae spp.e.g. Stomoxys calcitrans and Haematobia irritans, Hypoderma spp.,Gastrophilus spp., Simulium spp.); Hemiptera (e.g. Triatoma spp.);Phthiraptera (e.g. Damalinia spp., Linognathus spp.); Siphonaptera(e.g.Ctenocephalides spp.); Dictyoptera (e.g. Periplaneta spp., Blatellaspp.) and Hymenoptera(e.g. Monomorium pharaonis). The compounds of thepresent invention also have utility in the field of control of plantpests, soil inhabiting pests and other environmental pests.

The present invention is particularly useful in the control of arthropodpests in mammals, in particular humans and animals. Preferably thisinvention is useful in the control of arthropod pests in animals whichincludes livestock such as cattle, sheep, goats, equines, swine andcompanion animals such as dogs and cats.

The compounds of the invention are of particular value in the control ofarthropods which are injurious to, or spread or act as vectors ofdiseases in, man and domestic animals, for example those hereinbeforementioned, and more especially in the control of ticks, mites, lice,fleas, midges and biting, nuisance and myiasis flies. They areparticularly useful in controlling arthropods which are present insidedomestic host animals or which feed in or on the skin or suck the bloodof the animal, for which purpose they may be administered orally,parenterally, percutaneously or topically.

The compounds of the invention are of value for the treatment andcontrol of the various lifecycle stages of parasites including egg,nymph, larvae, juvenile and adult stages.

According to another aspect of the present invention, there is provideda method for the control of arthropod pests of insects which comprisestreatment of the insect with an effective amount of a compound ofgeneral formula (I), or a pesticidally acceptable salt thereof.Compounds of the present invention may also be used for the treatment ofinfections caused by mites, and in particular varoaa mites. Inparticular compounds of the present invention may also be used for thetreatment of varoaa mite infection in bees.

According to another aspect of the present invention, there is provideda method for the control of arthropod pests of plants which comprisestreatment of the plant with an effective amount of a compound of generalformula (I), or a pesticidally acceptable salt thereof. The compounds ofthe invention also have utility in the control of arthropod pests ofplants. The active compound is generally applied to the locus at whichthe arthropod infestation is to be controlled at a rate of about 0.005kg to about 25 kg of active compound per hectare (ha) of locus treated,preferably 0.02 to 2 kg/ha. Under ideal conditions, depending on thepest to be controlled, the lower rate may offer adequate protection. Onthe other hand, adverse weather conditions and other factors may requirethat the active ingredient be used in higher proportions. For foliarapplication, a rate of 0.01 to 1 kg/ha may be used. Preferably, thelocus is the plant surface, or the soil around the plant to be treated.

According to another aspect of the present invention, there is provideda method for the protection of timber which comprises treatment of thetimber with an effective amount of a compound of general formula (I), ora pesticidally acceptable salt thereof. Compounds of the presentinvention are also valuable in the protection of timber (standing,felled, converted, stored or structural) from attack by sawflies orbeetles or termites. They have applications in the protection of storedproducts such as grains, fruits, nuts, spices and tobacco, whetherwhole, milled or compounded into products, from moth, beetle and miteattack. Also protected are stored animal products such as skins, hair,wool and feathers in natural or converted form (e.g. as carpets ortextiles) from moth and beetle attack; also stored meat and fish frombeetle, mite and fly attack. Solid or liquid compositions forapplication topically to timber, stored products or household goodsusually contain from about 0.00005% to about 90%, more particularly fromabout 0.001% to about 10%, by weight of one or more compounds of formula(I) or pesticidally acceptable salts thereof.

The liquid compositions of this invention may, in addition to normalagricultural use applications be used for example to treat substrates orsites infested or liable to infestation by arthropods (or other pestscontrolled by compounds of this invention) including premises, outdooror indoor storage or processing areas, containers or equipment orstanding or running water.

The present invention also relates to a method of cleaning animals ingood health comprising the application to the animal of compound offormula (I) or a veterinarily acceptable salt. The purpose of suchcleaning is to reduce or eliminate the infestation of humans withparasites carried by the animal and to improve the environment in whichhumans inhabit.

The biological activity of the compounds was tested using one or more ofthe test methods outlined below.

In Vitro Tick Assay

Application of octopamine agonists to acarids for example, ticks, causesdistinct behavioural changes compared to untreated control ticks.Treated ticks become agitated and move constantly, this prevents ticksattaching and feeding on a host animal to which the compound has beenapplied. Normal behaviour of ticks is to go into stasis when all otherexternal stimuli are removed. Agitation and movement can be measured invitro in the laboratory to predict efficacy and potency in vivo.

The assay was run using unfed Rhipicephalus sanguineus (brown dog tick)and precoated glass vials with an inner surface area of 34.5 cm². Eachcompound was tested in duplicate.

Compound (345 μg) was dissolved in isopropyl alcohol (500 μl) anddelivered to each vial. The vials were placed on a tilting roller in afume hood for 2 hours to allow the isopropyl alcohol to evaporate givinga compound concentration for each vial of 10 μg/cm². Five R. sanguineus(male and female) were added to each coated vial and the vial sealedwith a firm wad of cotton wool. Vials were then kept, undisturbed, onthe bench at room temperature. Observation and recordings of activitywere taken at 24, 48 and 72 hours after addition of ticks to the vials.The ED₁₀₀ value was determined as the lowest dose at which all fiveticks were seen moving around inside the vial.

Octopamine Activity

One skilled in the art could determine agonist activity of compoundsagainst insect octopamine receptors expressed in CHO cells by adaptingthe methods described in B. Maqueira, H. Chatwin, P. D. Evans, J.Neurochemistry, 2005, 94, 2, 547. Compound activity can be measured asan increase in cAMP by various methods known to a skilled person and canbe recorded as % Vmax (Vmax=maximal octopamine response) and EC₅₀.

Adrenergic Activity

Methods from literature procedures were simply adapted, as could bereadily performed by one skilled in the art, in order to determine α2adrenergic activity of the compounds. Suitable procedures include thosedescribed in J J. Meana, F. Barturen, J. A. Garcia-Sevilla, Journal ofNeurochemistry, 1989, 1210; and D. J. Loftus, J. M. Stolk, D. C.U'Pritchard, Life Sciences, 1984, 35, 610.

EXAMPLES

The following Examples illustrate the preparation of compounds of theformula (I).

In the following Examples, structures are depicted as follows:

Unless specified otherwise, the wedge and dashed bonds indicate absolutestereochemistry as drawn at this chiral centre, a wiggly bond indicatesthat the absolute stereochemistry is unknown but the compound is asingle stereoisomer at this chiral centre. Straight bonds emanating froma chiral centre indicate that the stereoisomers are not resolved and amixture of stereoisomers is present.

When the source of a simple precursor is unspecified these compounds maybe obtained from commercial suppliers or according to literatureprocedures. The following is a list of commercial suppliers for suchcompounds:

-   Sigma-Aldrich, PO Box 14508, St. Louis, Mo., 63178, USA-   Lancaster Synthesis Ltd., Newgate, White Lund, Morecambe,    Lancashire, LA3 3BN, UK-   Maybridge, Trevillett, Tintagel, Cornwall, PL34 0HW, UK-   Fluorochem Ltd., Wesley Street, Old Glossop, Derbyshire, SK13 7RY,    UK-   ASDI Inc, 601 Interchange Blvd., Newark, Del., 19711, USA-   Alfa Aesar, 26 Parkridge Road, Ward Hill, Mass., 01835, USA-   Bionet Research Ltd., Highfield Industrial Estate, Camelford,    Cornwall, PL32 9QZ, UK-   Acros Organics, Janssens Pharmaceuticalaan 3A, Geel, 2440, Belgium-   Apin Chemicals Ltd., 3D Milton Park, Abingdon, Oxfordshire, OX14    4RU, UK-   Pfaltz & Bauer, Inc., 172 East Aurora Street, Waterbury, Conn.    06708, USA-   Trans World Chemicals, Inc., 14674 Southlawn Lane, Rockville, Md.    20850, USA-   Peakdale Molecular Ltd., Peakdale Science Park, Sheffield Road,    Chapel-en-le-Frith, High Peak, SK23 0PG, UK-   TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA-   Fluka Chemie GmbH, Industriestrasse 25, P.O. Box 260, CH-9471 Buchs,    Switzerland-   JRD Fluorochemicals Ltd., Unit 11, Mole Business Park, Leatherhead,    Surrey, KT22 7BA, UK    Instruments Used

In the following experimental details, nuclear magnetic resonancespectral data were obtained using Varian Inova 300, Varian Inova 400,Varian Mercury 400, Varian Unityplus 400, Bruker AC 300 MHz, Bruker AM250 MHz or Varian T60 MHz spectrometers, the observed chemical shiftsbeing consistent with the proposed structures. N.m.r chemical shifts arequoted in p.p.m downfield from tetramethylsilane. Mass spectral datawere obtained on a Finnigan ThermoQuest Aqa, a Waters micromass ZQ,Bruker APEX II FT-MS or a Hewlett Packard GCMS System Model 5971spectrometer. The calculated and observed ions quoted refer to theisotopic composition of lowest mass. HPLC means high performance liquidchromatography. Analytical HPLC data was collected on a HP1100 SeriesHPLC system. Preparative HPLC data was collected using a GilsonPreparative HPCL system.

CHN microanalysis data were collected using Exeter Analytical CE 440instruments by Warwick Analytical Service, (University of WarwickScience Park, Barclays Venture Centre, Sir William Lyons Road, Coventry,CV4 7EZ).

Optical rotation data was collected using a Perkin Elmer Polarimeter 341by Warwick analytical Service, (University of Warwick Science Park,Barclays Venture Centre, Sir William Lyons Road, Coventry, CV4 7EZ).

Example 1 2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole

A solution of the compound of Preparation 194 (11.0 g, 38.1 mmol) andpalladium(II) hydroxide (1.10 g, 7.83 mmol) in methanol (100 ml) washeated to 60° C. at a pressure of 300 psi under a hydrogen atmospherefor 18 h. The reaction mixture was then filtered and concentrated invacuo and the residue was re-crystallised from hot acetonitrile (50 ml)to give the title compound (3.27 g).

Experimental MH⁺ 201.3; expected 201.1 ¹H-NMR (CD₃OD): 1.50-1.55 (3H),2.15-2.20 (3H), 2.20-2.25 (3H), 4.40-4.50 (1H), 6.80-6.85 (1H),6.90-6.92 (2H), 6.95-7.00 (2H) Rhip. Funct. ED₁₀₀ mg/cm²=0.1

Alternative Synthesis

A solution of the compound of Preparation 1 (72 mg, 0.36 mmol) inmethanol (5 ml) was hydrogenated at 100 psi and 60° C. using palladium(10 wt % on carbon, 10 mg), overnight. The mixture was filtered and thefiltrate concentrated in vacuo. The residue was dissolved in methanol (1ml) and diethylamine (2-3 drops, 1 ml) and purified by automatedpreparative liquid chromatography (Gilson system, 150 mm×30 mm LUNAC18(2) 10 μm column, 40 ml/min) using an acetonitrile:water gradient[30:70 to 98:2]. The appropriate fractions were concentrated in vacuo togive the title compound (26 mg).

Experimental MH⁺ 201.2; expected 201.1 ¹H-NMR (d₆-DMSO): 1.65-1.72 (3H),2.13-2.18 (3H), 2.24-2.31 (3H), 4.43-4.52 (1H), 6.89-6.92 (2H),7.00-7.03 (1H), 7.03-7.11 (2H)

Alternative Synthesis

To a mixture of the compound of Preparation 1 (1.0 g, 3.26 mmol) andammonium formate (1.0 g, 15.9 mmol) in formic acid (20 ml) was addedpalladium (10% wt % on carbon, 1.0 g). The reaction mixture was heatedat 100° C. for 72 h, filtered and concentrated in vacuo. The residue wastriturated with methanol:ethyl acetate [1:9] to give the title compound(200 mg).

Experimental MH⁺ 201.3; expected 201.1 ¹H-NMR (CD₃OD): 1.65-1.70 (3H),2.20-2.25 (3H), 2.25-2.30 (3H), 4.80-4.90 (1H), 6.80-6.85 (1H),7.00-7.10 (2H), 7.35-7.40 (2H)

Alternative Synthesis

A mixture of the crude compound of Preparation 13 (500 mg, 2.3 mmol) andpalladium (10 wt % on carbon, 223 mg) in formic acid (10 ml) was heatedat reflux for 36 h. The reaction mixture was filtered and the filtratewas concentrated in vacuo to give the crude title compound

Experimental MH⁺ 201.3; expected 201.1

Example 2 2-{1-[2-Methyl-3-(trifluoromethyl)phenyl]ethyl}-1H-imidazole

A mixture of the compound of Preparation 148 (2.0 g, 5.8 mmol) andpalladium (10 wt % on carbon, 500 mg) in methanol (25 ml) was heated at60° C. under a hydrogen atmosphere (150 psi) for 24 h. The mixture wasfiltered through Arbocel® and the filtrate was concentrated in vacuo.

The residue was purified by flash chromatography (silica), eluting withmethanol. The appropriate fractions were combined and concentrated togive the title compound (11 mg).

¹H-NMR (CD₃OD): 1.58-1.62 (3H), 2.40-2.43 (3H), 4.56-4.62 (1H),6.90-6.94 (2H), 7.21-7.29 (2H), 7.47-7.51 (1H) Experimental MH⁺ 255.3;expected 255.1Rhip. Funct. ED₁₀₀ mg/cm²>1

Example 3 2-[1-(1H-Imidazol-2-yl)ethyl]-6-methylbenzonitrile

To a solution of the compound of Preparation 167 (50 mg, 0.17 mmol) in2-propanol (2 ml) was added ammonium formate (105 mg, 1.67 mmol) andpalladium (10 wt % on carbon, 36 mg). The reaction mixture was heated at80° C., under nitrogen, for 2 h and then cooled. The mixture wasfiltered through Arbocel®, washing through with 2-propanol, and thefiltrate was concentrated in vacuo.

The residue was dissolved in acetonitrile:water (9:1, 4 ml) and purifiedby automated preparative liquid chromatography (Gilson system, 150 mm×30mm LUNA C18(2) 10 μm column, 40 ml/min) using an acetonitrile:watergradient [30:70 (20 min) to 95:5 (21 min)]. The appropriate fractionswere combined and concentrated to give the title compound (8 mg).

Experimental MH⁺ 212.1; expected 212.1 ¹H-NMR (d₆-Acetone): 1.64-1.66(3H), 2.50-2.51 (3H), 4.59-4.61 (1H), 6.90-7.05 (2H), 7.19-7.21 (1H),7.23-7.25 (1H), 7.42-7.45 (1H) Rhip. Funct. ED₁₀₀ mg/cm²=0.3

Similarly prepared were:

Ex. From MH⁺ Found/ Rhip. Funct. No. Ar Name Prep. Expected ED₁₀₀ mg/cm²4

2-[1-(3-Ethylphenyl)ethyl]-1H- imidazole 146 201.3 201.1 >1 5

2-[1-(3-Cyclopropylphenyl)- ethyl]-1H-imidazole 138 213.2 213.1 >10 6

2-(1-Biphenyl-3-ylethyl)-1H- imidazole 137 249.4 249.1 <=10 7

2-[1-(2-Fluoro-3-methylphenyl)- ethyl]-1H-imidazole 143 205.2 205.1 0.1,0.3, <=0.03 8

2-{1-[2-Methyl-5- (trifluoromethyl)phenyl]-ethyl}- 1H-imidazole 144255.3 255.1 >1 9

2-[1-(3-Ethyl-2-methylphenyl)- ethyl]-1H-imidazole 176 215.4 215.2 1 10

3-[1-(1H-Imidazol-2-yl)ethyl]-5- methylbenzonitrile 169 212.3 212.1 <=1011

3-[1-(1H-Imidazol-2-yl)ethyl]-2- methylbenzonitrile 168 212.2 212.1 <=1012

2-{1-[2-(Difluoromethyl)-3- methylphenyl]ethyl}-1H- imidazole 181 237.2237.1 >1

Example 4

¹H-NMR (CDCl₃): 1.14-1.21 (3H), 1.62-1.70 (3H), 2.53-2.62 (2H),4.15-4.22 (1H), 6.80-6.85 (2H), 6.97-7.02 (2H), 7.02-7.07 (1H),7.15-7.21 (1H)

Example 5

¹H-NMR (d₆-DMSO): 0.58-0.62 (2H), 0.83-0.87 (2H), 1.50-1.54 (3H),1.80-1.84 (1H), 4.03-4.05 (1H), 6.80-6.88 (3H), 6.95-6.98 (3H),7.10-7.14 (1H)

Example 6

¹H-NMR (CD₃OD): 1.68-1.74 (3H), 4.25-4.34 (1H), 6.95-6.97 (2H),7.19-7.21 (1H), 7.27-7.45 (6H), 7.55-7.59 (2H)

Example 7

¹H-NMR (d₆-DMSO): 1.42-1.50 (3H), 2.15-2.20 (3H), 4.37-4.41 (1H),6.71-6.75 (1H), 6.89-6.98 (3H), 7.03-7.06 (1H)

Example 8

¹H-NMR (CD₃OD): 1.61-1.65 (3H), 2.39-2.42 (3H), 4.51-4.58 (1H),6.94-6.98 (2H), 7.32-7.36 (2H), 7.37-7.41 (1H)

Example 9

¹H-NMR (d₆-Acetone): 1.11-1.19 (3H), 1.55-1.59 (3H), 2.26-2.28 (3H),2.60-2.68 (2H), 4.45-4.52 (1H), 6.89-6.93 (2H), 6.97-7.01 (3H)

Example 10

¹H-NMR (CDCl₃): 1.65-1.71 (3H), 2.35-2.38 (3H), 4.19-4.24 (1H),6.98-7.00 (2H), 7.28-7.34 (3H)

Example 11

¹H-NMR (d₆-Acetone): 1.60-1.63 (3H), 2.58-2.59 (3H), 4.55-4.50 (1H),6.90-6.95 (2H), 7.29-7.33 (1H), 7.50-7.60 (2H)

Example 12

¹H-NMR (CDCl₃): 1.70-1.75 (3H), 2.32-2.34 (3H), 4.54-4.60 (1H),6.91-6.93 (2H), 7.21-7.25 (3H)

Example 13 1-Benzyl-2-{1-[3-(difluoromethyl)phenyl]ethyl}-1H-imidazole

To a solution of the compound of Preparation 142 (100 mg, 0.32 mmol) in2-propanol (4 ml) was added ammonium formate (406 mg, 6.44 mmol) andpalladium (10 wt % on carbon, 137 mg). The reaction mixture was heatedat 80° C., under nitrogen, for 18 h and then cooled. The mixture wasfiltered through Arbocel®, washing through with 2-propanol, and thefiltrate was concentrated in vacuo.

The residue was dissolved in acetonitrile:water (9:1, 4 ml) and purifiedby automated preparative liquid chromatography (Gilson system, 100 mm×30mm LUNA C18(2) 5 μm column, 40 ml/min) using an acetonitrile:watergradient [40:60 (20 min) to 95:5 (25 min)]. The appropriate fractionswere combined and concentrated to give the title compound (8 mg).

Experimental MH⁺ 313.4; expected 313.2 ¹H-NMR (d₆-Acetone): 1.58-1.61(3H), 4.25-4.31 (1H), 4.99-5.03 (1H), 5.10-5.14 (1H), 6.80-6.82 (1H),6.94-6.98 (3H), 7.00-7.02 (1H), 7.20-7.25 (3H), 7.38-7.41 (4H) Rhip.Funct. ED₁₀₀ mg/cm²=>1

Similarly prepared was:

Rhip. MH⁺ Funct. Ex. Found/ ED₁₀₀ No. Ar Name From Prep. Expected mg/cm²14

1-Benzyl-2-{1-[2-(difluoromethyl)- 3-methylphenyl]ethyl}-1H- imidazole181 327.2 327.2 >1

Example 14

¹H-NMR (CD₃OD): 1.59-1.62 (3H), 2.30-2.31 (3H), 4.54-4.59 (1H),6.80-6.83 (3H), 6.88-6.90 (1H), 7.00-7.02 (2H), 7.15-7.17 (1H),7.18-7.20 (2H), 7.26-7.27 (1H)

Example 15 2-[1-(2-Methyl-3-propylphenyl)ethyl]-1H-imidazole

To a solution of the compound of Preparation 136 (720 mg, 2.3 mmol) in2-propanol (20 ml) was added ammonium formate (1.0 g, 20 mmol) andpalladium (10 wt % on carbon, 300 mg). The reaction mixture was heatedat 80° C., under nitrogen, for 72 h and then cooled. The mixture wasfiltered through Arbocel®, washing through with 2-propanol, and thefiltrate was concentrated in vacuo. The residue was dissolved inacetonitrile (2 ml) and diethylamine (2-3 drops) and purified byautomated preparative liquid chromatography (Gilson system, 150 mm×50 mmLUNA C18(2) AX 5 μm column, 40 ml/min) using an acetonitrile:watergradient [40:60 (15 min) to 95:5 (15.5 min)]. The appropriate fractionswere combined and concentrated to give the title compound (74 mg).

Experimental MH⁺ 229.3; expected 229.2 ¹H-NMR (d₆-Acetone): 0.95-1.00(3H), 1.51-1.60 (5H), 2.13-2.15 (3H), 2.58-2.61 (2H), 4.47-4.52 (1H),6.85-6.90 (2H), 6.96-7.00 (3H) Rhip. Funct. ED₁₀₀ mg/cm²=<=10

Example 16 2-{1-[2-(Trifluoromethyl)phenyl]ethyl}-1H-imidazole

A mixture of the compound of Preparation 51 (212 mg, 0.88 mmol) andpalladium (10 wt % on carbon, 500 mg) in methanol (10 ml) was heated at60° C. under a hydrogen atmosphere (150 psi) for 60 h. The mixture wasfiltered through Arbocel® and the filtrate was concentrated in vacuo.The residue was dissolved in methanol (2 ml) diethylamine (2-3 drops)and purified by automated preparative liquid chromatography (Gilsonsystem, 150 mm×50 mm LUNA C18(2) 10 μm column, 40 ml min) using anacetonitrile:water gradient [35:65 to 95:5]. The appropriate fractionswere concentrated in vacuo to give the title compound (58 mg).

Experimental MH⁺ 241.3; expected 241.1 ¹H-NMR (CD₃OD): 1.60-1.66 (3H),4.53-4.61 (1H), 6.88-6.95 (2H), 7.31-7.39 (2H), 7.48-7.53 (1H),7.62-7.68 (1H) Rhip. Funct. ED₁₀₀ mg/cm²=3

Similarly prepared were:

Ex. From MH⁺ Found/ Rhip. Funct. No. Ar Name Prep. Expected ED₁₀₀ mg/cm²17

2-[1-(2,5-Dimethyl- phenyl)ethyl]-1H- imidazole 49 201.4 201.1 >10 18

2-[1-(2,6-Dimethyl- phenyl)ethyl]-1H- imidazole 66 201.3 201.1 >1 19

2-[1-(3,5-Dimethyl- phenyl)ethyl]-1H- imidazole 50 201.4 201.1 0.3, 1 20

2-[1-(3-Methylphenyl)- ethyl]-1H-imidazole 48 187.3 187.1 0.1 21

2-(1-Phenylethyl)-1H- imidazole 57 173.2 173.1 1 22

2-[1-(4-Methylphenyl)- ethyl]-1H-imidazole 58 187.3 187.1 >1 23

2-(1-Mesitylethyl)-1H- imidazole 59 215.4 215.2 >1 24

2-{1-[3-(Trifluoromethyl)- phenyl]ethyl}-1H- imidazole 60 241.3 241.1 >125

2-{1-[4-(Trifluoromethyl)- phenyl]ethyl}-1H- imidazole 61 241.3 241.1 >126

2-[1-(3-Methoxy-2- methylphenyl)ethyl]-1H- imidazole 62 217.3 217.1 >127

2-[1-(2-Ethyl-3-methyl- phenyl)ethyl]-1H- imidazole 63 215.3 215.2 <=1028

2-{1-[3-(Trifluorometh- oxy)phenyl]ethyl}-1H- imidazole 65 257.1 257.1<=10 29

2-[1-(2,6-Difluoro-3- methylphenyl)ethyl]-1H- imidazole 73 223.2223.1 >1 30

2-[1-(3,5-Difluoro- phenyl)ethyl]-1H- imidazole 10 209.2 209.1 >1 31

2-{1-[2-Fluoro-3- (trifluoromethyl)phenyl]- ethyl}-1H-imidazole 12 259.1259.1 >1

Example 17

¹H-NMR (d₆-Acetone): 1.60-1.70 (3H), 2.08-2.15 (3H), 2.21-2.30 (3H),4.40-4.50 (1H), 6.81-6.92 (2H), 6.93-6.99 (1H), 7.00-7.08 (2H)

Example 18

¹H-NMR (CDCl₃): 1.68-1.72 (3H), 2.04-2.12 (6H), 4.49-4.55 (1H),6.86-6.91 (2H), 6.95-6.98 (2H), 7.00-7.05 (1H)

Example 19

¹H-NMR (CD₃OD): 1.55-1.60 (3H), 2.19-2.21 (6H), 4.05-4.15 (1H),6.75-7.80 (3H), 6.85-6.90 (2H)

Example 20

¹H-NMR (CDCl₃): 1.67-1.71 (3H), 2.28-2.30 (3H), 4.12-4.18 (1H),6.90-6.93 (2H), 7.00-7.06 (2H), 7.17-7.23 (2H)

Example 21

¹H-NMR (CDCl₃): 1.67-1.72 (3H), 4.14-4.21 (1H), 6.89-6.94 (2H),7.18-7.25 (3H), 7.26-7.33 (2H)

Example 22

¹H-NMR (CDCl₃): 1.67-1.70 (3H), 2.29-2.31 (3H), 4.12-4.18 (1H),6.89-6.92 (2H), 7.10-7.12 (4H)

Example 23

¹H-NMR (CD₃OD): 1.55-1.65 (3H), 2.00-2.10 (3H), 2.14-2.17 (3H),2.18-2.20 (3H), 4.40-4.50 (1H), 6.80-6.90 (1H), 6.90-6.95 (3H)

Example 24

¹H-NMR (CDCl₃): 1.69-1.73 (3H), 4.23-4.30 (1H), 6.92-6.97 (2H),7.31-7.35 (2H), 7.52-7.56 (2H)

Example 25

¹H-NMR (CDCl₃): 1.69-1.74 (3H), 4.22-4.30 (1H), 6.92-6.97 (2H),7.31-7.35 (2H), 7.52-7.56 (2H)

Example 26

¹H-NMR (CDCl₃): 1.64-1.68 (3H), 2.09-2.13 (3H), 3.77-3.81 (3H),4.38-4.45 (1H), 6.72-6.77 (2H), 6.87-6.89 (2H), 7.09-7.15 (1H)

Example 27

¹H-NMR (CD₃OD): 1.03-1.09 (3H), 1.58-1.63 (3H), 2.29-2.31 (3H),2.65-2.75 (2H), 4.42-4.48 (1H), 6.82-6.85 (2H), 6.92-7.00 (3H)

Example 28

¹H-NMR (CD₃OD): 1.60-1.65 (3H), 4.20-4.26 (1H), 6.90-6.93 (2H),7.03-7.06 (2H), 7.18-7.20 (1H), 7.33-7.37 (1H)

Example 29

¹H-NMR (CDCl₃): 1.68-1.72 (3H), 2.17-2.20 (3H), 4.60-4.65 (1H),6.70-6.75 (1H), 6.90-6.93 (2H), 6.95-7.00 (1H)

Example 32 2-[1-(2,3,5-Trimethylphenyl)ethyl]-1H-imidazole

A mixture of the compound of Preparation 64 (150 mg, 0.52 mmol) andpalladium (10 wt % on carbon, 15 mg) in 2-propanol (5 ml) was heated at60° C. under a hydrogen atmosphere (200 psi) for 18 h. The mixture wasfiltered through Arbocel® and the filtrate was concentrated in vacuo.The residue was dissolved in acetonitrile (1.22 ml) and diethylamine(2-3 drops) and purified by automated preparative liquid chromatography(Gilson system, 150 mm×50 mm LUNA C18(2) 5 μm column, 40 ml/min) usingan acetonitrile:water gradient [32:68 (20 min) to 95:5 (21 min)]. Theappropriate fractions were combined and concentrated to give the titlecompound (30 mg).

Experimental MH⁺ 215.4; expected 215.2 ¹H-NMR (CD₃OD): 1.57-1.60 (3H),2.15-2.19 (6H), 2.20-2.22 (3H), 4.35-4.39 (1H), 6.80-6.82 (1H),6.87-6.90 (3H) Rhip. Funct. ED₁₀₀ mg/cm²=>1

Example 33 2-[1-(2,3-Dimethylphenyl)propyl]-1H-imidazole

A mixture of the compound of Preparation 47 (255 mg, 1.2 mmol) andpalladium (10 wt % on carbon, 50 mg) in 2-propanol (50 ml) was heated at40° C. under a hydrogen atmosphere (200 psi) for 18 h. The mixture wasfiltered through Arbocel® and the filtrate was concentrated in vacuo.The residue was re-crystallised from warm diethyl ether (5 ml) and thesolid was triturated with further diethyl ether (5 ml) to give the titlecompound (175 mg).

Experimental MH⁺ 215.3; expected 215.2 ¹H-NMR (CDCl₃): 0.87-0.95 (3H),1.90-2.03 (1H), 2.11-2.16 (3H), 2.23-2.27 (3H), 2.28-2.38 (1H),4.19-4.25 (1H), 6.85-6.90 (2H), 7.01-7.07 (3H) Rhip. Funct. ED₁₀₀mg/cm²=1

Example 34 2-[1-(2-Chloro-3-methylphenyl)ethyl]-1H-imidazole

A mixture of the compound of Preparation 67 (1.51 g, 6.8 mmol) andpalladium hydroxide (20 wt % Pd on carbon, 500 mg) in 2-propanol (100ml) was heated at 50° C. under a hydrogen atmosphere (200 psi) for 18 h.The mixture was filtered through Arbocel® and the filtrate wasconcentrated in vacuo. The residue was dissolved in acetonitrile (1 ml)and diethylamine (2-3 drops) and purified by automated preparativeliquid chromatography (Gilson system, 100 mm×30 mm LUNA C18(2) 10 μmcolumn, 40 ml/min) using an acetonitrile:water gradient [35:65 (15 min)to 95:5 (15.5 min)]. The appropriate fractions were combined andconcentrated to give the title compound (21 mg).

Experimental MH⁺ 221.3; expected 221.1 ¹H-NMR (d₆-DMSO): 1.49-1.53 (3H),2.34-2.37 (3H), 4.58-4.62 (1H), 6.79-6.81 (1H), 6.95-7.00 (2H),7.10-7.13 (1H), 7.18-7.20 (1H) Rhip. Funct. ED₁₀₀ mg/cm²=0.1

Similarly prepared were:

MH⁺ Rhip. Funct. Ex. From Found/ ED₁₀₀ No. Ar Name Prep. Expected mg/cm²35

2-[1-(2,4-Dichloro- phenyl)ethyl]-1H- imidazole 56 241.2 241.0 >1 36

2-[1-(4-Chloro-3-methyl- phenyl)ethyl]-1H- imidazole 74 221.3 221.1 >1037

2-[1-(2,3-Dichloro- phenyl)ethyl]-1H- imidazole 52 241.2 241.0 >1 38

2-[1-(3,4-Dichloro- phenyl)ethyl]-1H- imidazole 53 241.2 241.0 3 39

2-[1-(3-Chlorophenyl)- ethyl]-1H-imidazole 54 201.3 201.3 >1 40

2-[1-(2-chloro-4- Methoxyphenyl)ethyl]- 1H-imidazole 75 237.3 237.1 >141

2-[1-(3-Chloro-2- methoxyphenyl)ethyl]- 1H-imidazole 77 237.3 237.1 >142

2-[1-(3-Chloro-4- methoxyphenyl)ethyl]- 1H-imidazole 76 237.3 237.1 >143

2-[1-(2,5-Dichloro- phenyl)ethyl]-1H- imidazole 55 241.2 241.0 >1 44

2-[1-(3-Chloro-4-methyl- phenyl)ethyl]-1H- imidazole 68 221.3 221.1 >145

2-[1-(3-Chloro-2-methyl- phenyl)ethyl]-1H- imidazole 69 221.3 221.1 >146

2-[1-(2-Chloro-5- methoxyphenyl)ethyl]- 1H-imidazole 70 237.2 237.1 <=1047

2-[1-(2-Chloro-5-methyl- phenyl)ethyl]-1H- imidazole 71 221.3 221.1 —

Example 36

¹H-NMR (CD₃OD): 1.53-1.62 (3H), 2.20-2.28 (3H), 4.10-4.20 (1H),6.83-6.92 (2H), 6.92-6.99 (1H), 7.06-7.11 (1H), 7.14-7.21 (1H)

Example 38

¹H-NMR (CD₃OD): 1.60-1.65 (3H), 4.20-4.30 (1H), 6.90-7.00 (2H),7.10-7.15 (1H), 7.36-7.40 (1H), 7.40-7.44 (1H)

Example 39

¹H-NMR (CD₃OD): 1.60-1.63 (3H), 4.20-4.24 (1H), 6.95-6.97 (2H),7.14-7.16 (1H), 7.19-7.27 (3H)

Example 40

¹H-NMR (d₆-Acetone): 1.55-1.65 (3H), 3.75-3.81 (3H), 5.18-5.25 (1H),6.80-6.85 (1H), 6.95-6.98 (1H), 7.10-7.20 (2H), 7.35-7.40 (1H)

Example 43

¹H-NMR (CD₃OD): 1.58-1.61 (3H), 4.60-4.64 (1H), 6.95-6.97 (2H),7.07-7.08 (1H), 7.18-7.20 (1H), 7.37-7.39 (1H)

Example 44

¹H-NMR (CD₃OD): 1.58-1.61 (3H), 2.24-2.26 (3H), 4.15-4.20 (1H),6.89-6.91 (2H), 7.00-7.02 (1H), 7.17-7.19 (2H)

Example 46

¹H-NMR (CD₃OD): 1.57-1.60 (3H), 3.62-3.63 (3H), 4.60-4.65 (1H),6.60-6.61 (1H), 6.72-6.75 (1H), 6.91-6.93 (2H), 7.21-7.24 (1H)

Example 48 2-[1-(2,3-Difluorophenyl)ethyl]-1H-imidazole

To a solution of the compound of Preparation 2 (320 mg, 1.55 mmol) in2-propanol (20 ml) was added ammonium formate (1.47 g, 23.3 mmol) andpalladium (10 wt % on carbon, 495 mg). The reaction mixture was heatedat 80° C. for 18 h and then cooled. The mixture was filtered throughArbocel®, washing through with 2-propanol (10 ml), and the filtrate wasconcentrated in vacuo. The residue was dissolved in acetonitrile (2 ml)and purified by automated preparative liquid chromatography (Gilsonsystem, 150 mm×50 mm LUNA C18(2) 10 μm column, 40 ml/min) using anacetonitrile:water gradient [30:70 (20 min) to 95:5 (21 min)]. Theappropriate fractions were combined and concentrated to give the titlecompound (10 mg).

Experimental MH⁺ 209.4; expected 209.1 ¹H-NMR (CD₃OD): 1.62-1.65 (3H),4.54-4.61 (1H), 6.90-6.96 (2H), 7.02-7.25 (3H) Rhip. Funct. ED₁₀₀mg/cm²=3

Similarly prepared were:

MH⁺ Rhip. Funct. Ex. From Found/ ED₁₀₀ No. Ar Name Prep. Expected mg/cm²49

2-[1-(5-Methoxy-2,4- dimethylphenyl)ethyl]- 1H-imidazole 11 231.2 231.1<=10 50

2-[1-(4-Fluoro-3-methyl- phenyl)ethyl]-1H- imidazole 4 205.2 205.1 >1 51

2-[1-(2,6-Difluoro- phenyl)ethyl]-1H- imidazole 5 209.2 209.1 >1 52

2-[1-(3-Fluoro-2-methyl- phenyl)ethyl]-1H- imidazole 6 205.3 205.1 >1 53

2-[1-(3-Fluorophenyl)- ethyl]-1H-imidazole 7 191.3 191.1 >1 54

2-{1-[2-Chloro-3- (trifluoromethyl)phenyl]- ethyl}-1H-imidazole 8 275.1275.1 >1 55

2-[1-(3-Fluoro-5-methyl- phenyl)ethyl]-1H- imidazole 9 205.3 205.1 0.356

2-{1-[3-Methyl-2- (trifluoromethyl)phenyl]- ethyl}-1H-imidazole 72 255.3255.1 >1

Example 49

¹H-NMR (d₆-DMSO): 1.45-1.49 (3H), 2.00-2.02 (3H), 2.19-2.21 (3H),3.60-3.61 (3H), 4.23-4.27 (1H), 6.70-6.72 (1H), 6.77-6.79 (1H),6.83-6.85 (1H), 6.92-6.95 (1H)

Example 50

¹H-NMR (CDCl₃): 1.62-1.67 (3H), 2.15-2.20 (3H), 4.19-4.24 (1H),6.82-6.87 (3H), 6.97-7.01 (2H)

Example 51

¹H-NMR (CDCl₃): 1.75-1.80 (3H), 4.68-4.73 (1H), 6.82-6.87 (2H),6.94-6.96 (2H), 7.17-7.21 (1H)

Example 52

¹H-NMR (CDCl₃): 1.63-1.66 (3H), 2.18-2.20 (3H), 4.39-4.44 (1H),6.90-7.00 (4H), 7.10-7.15 (1H)

Example 53

¹H-NMR (CDCl₃): 1.70-1.74 (3H), 4.18-4.23 (1H), 6.90-7.00 (4H),7.00-7.02 (1H), 7.17-7.20 (1H)

Example 54

¹H-NMR (CDCl₃): 1.69-1.74 (3H), 4.79-4.85 (1H), 6.94-6.98 (2H),7.26-7.31 (1H), 7.41-7.44 (1H), 7.55-7.58 (1H)

Example 55

¹H-NMR (d₆-Acetone): 1.60-1.64 (3H), 2.25-2.27 (3H), 4.19-4.24 (1H),6.75-6.82 (2H), 6.85-6.98 (3H)

Example 56

¹H-NMR (CD₃OD): 1.60-1.64 (3H), 2.50-2.54 (3H), 4.63-4.67 (1H),6.90-6.93 (2H), 7.07-7.10 (1H), 7.18-7.20 (1H), 7.30-7.34 (1H)

Example 57 2-[1-(2-Fluoro-5-methylphenyl)ethyl]-1H-imidazole

A mixture of the compound of Preparation 3 (74 mg, 0.31 mmol), palladium(10 wt % on carbon, 140 mg) and ammonium formate (394 mg, 6.4 mmol) in2-propanol (20 ml) was heated at 80° C. for 24 h. The mixture wasfiltered through Arbocel® and the filtrate was concentrated in vacuo.The residue was dissolved in acetonitrile:methanol (1 ml) and purifiedby automated preparative liquid chromatography (Gilson system, 150 mm×30mm LUNA C18(2) 10 μm column, 40 ml/min) using an acetonitrile:watergradient [50:50 (20 min) to 98:2 (20.5 min)]. The appropriate fractionswere combined and concentrated to give the title compound (49 mg).

Experimental MH⁺ 205.1; expected 205.1 ¹H-NMR (d₆-Acetone): 1.60-1.63(3H), 2.20-2.22 (3H), 4.43-4.47 (1H), 6.84-6.86 (1H), 6.90-7.00 (2H),7.00-7.07 (2H) Rhip. Funct. ED₁₀₀ mg/cm²=>1

Example 58 2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole

The compound of Example 1 (750 mg, 3.75 mmol) was dissolved in ethanol(4 ml) and the enantiomers were separated by automated preparativeliquid chromatography (Gilson system, 50×50 mm ID Chiralcel OD, 20 μmcolumn, 50 ml/min) using ethanol:hexane [10:90] as the mobile phase. Theappropriate fractions were combined and concentrated to give the titlecompound (370 mg).

Retention time=5.79 min Chiralcel OD-H, 250×4.6 mm ID, 5 μm column,ethanol:hexane [10:90], 1 ml/min

Experimental MH⁺ 201.3; expected 201.1 ¹H-NMR (CD₃OD): 1.56-1.60 (3H),2.18-2.20 (3H), 2.22-2.24 (3H), 4.45-4.50 (1H), 6.80-6.86 (3H),6.95-6.99 (2H) Optical rotation, (25° C., methanol, 5.035 mg/ml, pathlength 100 mm): 365 nm=+266.93, 546 nm=+88.43, 589 nm=+73.58Rhip. Funct.ED₁₀₀ mg/cm²=0.1

Alternative Synthesis

To a solution of the compound of Preparation 1 (600 g, 3 mol) inmethanol (6.0 l) was added bis(norbornadiene)rhodium (I)tetrafluoroborate (1.50 g) and S(+)-1-[(R)-2-diphenylphosphinoferrocenyl]ethylditert.butylphosphine (2.61 g) and the reactionmixture was heated at 25° C., under a hydrogen atmosphere (45-60 psi),for 10 h. The reaction was monitored by HPLC, (upon completion: startingmaterial <0.1%, optical purity 93-94%). To the mixture was addedcharcoal (60 g) and the solution was stirred for 30 min. The mixture wasfiltered through Hyflo Super Cel®, washing through with methanol (2×300ml). To the filtrate was added di-p-toluoyl-L-tartaric acid (1.2 kg,3.08 mol). The reaction mixture was stirred at room temperature for 1 hand the solid material formed was collected by filtration. To the solidsalt was added dichloromethane (6.0 l) and aqueous sodium hydroxidesolution (1N, 6.0 l) and the reaction mixture was stirred for 30 min.The organic layer was separated and was washed with aqueous sodiumhydroxide solution (1N, 2×3.0 L). The organic layer was extracted withhydrochloric acid (1N, 3×2.0 L). The combined acidic aqueous layer wasadjusted to pH 10 by addition of aqueous sodium hydroxide solution (1N)and the resulting precipitate was collected by filtration and dried invacuo, at 50° C., to give the title compound (optical purity 98.58%).The process of di-p-toluoyl-L-tartaric acid salt formation andgeneration of free base was repeated once more to give the titlecompound (0.359 kg, optical purity 99.66%) after second resolution.

Example 59 2-[(1R)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole

The compound of Example 1 (750 mg, 3.75 mmol) was dissolved in ethanol(4 ml) and the enantiomers were separated by automated preparativeliquid chromatography (Gilson system, 50×50 mm ID Chiralcel OD, 20 μmcolumn, 50 ml/min) using ethanol:hexane [10:90] as the mobile phase. Theappropriate fractions were combined and concentrated to give the titlecompound (370 mg).

Retention time=7.84 min Chiralcel OD-H, 250×4.6 mm ID, 5 μm column,ethanol:hexane [10:90], 1 ml/min

Experimental MH⁺ 201.3; expected 201.1 ¹H-NMR (CD₃OD): 1.56-1.60 (3H),2.18-2.20 (3H), 2.22-2.24 (3H), 4.43-4.48 (1H), 6.80-6.86 (3H),6.95-6.99 (2H) Optical rotation, (25° C., methanol, 5.24 mg/ml, pathlength 100 mm): 365 nm=−262.79, 546 nm=−86.26, 589 nm=−72.23Rhip. Funct.ED₁₀₀ mg/cm²=>10

Example 60 2-[(1R*)-1-(3-Methylphenyl)ethyl]-1H-imidazole

The compound of Example 20 (40 mg, 0.22 mmol) was dissolved in ethanol(1 ml) and the enantiomers were separated by automated preparativeliquid chromatography (Gilson system, 250×20 mm ID Chiralpak AD-H, 5 μmcolumn, 15 ml/min) using ethanol:hexane [5:95] as the mobile phase. Theappropriate fractions were combined and concentrated to give the titlecompound (16 mg).

Retention time=7.93 min Chiralpak AD-H, 250×4.6 mm ID, 5 μm column,ethanol:hexane [10:90], 1 ml/min

Experimental MH⁺ 187.2; expected 187.1 ¹H-NMR (CD₃OD): 1.58-1.62 (3H),2.23-2.27 (3H), 4.12-4.18 (1H), 6.87-6.89 (2H), 6.94-7.01 (3H),7.09-7.14 (1H) Rhip. Funct. ED₁₀₀ mg/cm²=0.3

Example 61 2-[(1R*)-1-(3-Methylphenyl)ethyl]-1H-imidazole

The compound of Example 20 (40 mg, 0.22 mmol) was dissolved in ethanol(1 ml) and the enantiomers were separated by automated preparativeliquid chromatography (Gilson system, 250×20 mm ID Chiralpak AD-H, 5 μmcolumn, 15 ml/min) using ethanol:hexane [5:95] as the mobile phase. Theappropriate fractions were combined and concentrated to give the titlecompound (15 mg).

Retention time=6.06 min Chiralpak AD-H, 250×4.6 mm ID, 5 μm column,ethanol:hexane [10:90], 1 ml/min

Experimental MH⁺ 187.2; expected 187.1 ¹H-NMR (CD₃OD): 1.58-1.62 (3H),2.23-2.27 (3H), 4.12-4.18 (1H), 6.87-6.90 (2H), 6.94-7.00 (3H),7.09-7.14 (1H) Rhip. Funct. ED₁₀₀ mg/cm²=0.1

Example 62 1-Benzyl-2-[(1R*)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

The compound of Example 76 (540 mg, 1.8 mmol) was dissolved in ethanol(2 ml) and hexane (2 ml) and the enantiomers were separated by automatedpreparative liquid chromatography (Gilson system, 50×50 mm ID ChiralcelOD, 20 μm column, 40 ml/min) using ethanol:hexane [5:95] as the mobilephase. The appropriate fractions were combined and concentrated to givethe title compound (240 mg).

Retention time=5.82 min Chiralcel OD-H, 250×4.6 mm ID, 5 μm column,ethanol:hexane [10:90], 1 ml/min

Experimental MH⁺ 291.3; expected 291.1 ¹H-NMR (d₆-Acetone): 1.50-1.53(3H), 2.19-2.26 (6H), 4.31-4.36 (1H), 4.68-4.72 (1H), 4.90-4.94 (1H),6.70-6.72 (1H), 6.90-7.00 (6H), 7.20-7.25 (3H) Rhip. Funct. ED₁₀₀mg/cm²=0.3

Example 63 1-Benzyl-2-[1-(1R*)-(2,3-dimethylphenyl)ethyl]-1H-imidazole

The compound of Example 76 (540 mg, 1.8 mmol) was dissolved in ethanol(2 ml) and hexane (2 ml) and the enantiomers were separated by automatedpreparative liquid chromatography (Gilson system, 50×50 mm ID ChiralcelOD, 20 μm column, 40 ml/min) using ethanol:hexane [5:95] as the mobilephase. The appropriate fractions were combined and concentrated to givethe title compound (260 mg).

Retention time=8.80 min Chiralcel OD-H, 250×4.6 mm ID, 5 μm column,ethanol:hexane [10:90], 1 ml/min

Experimental MH⁺ 291.3; expected 291.1Rhip. Funct. ED₁₀₀ mg/cm²=>3

Example 64 2-[(1R*)-1-(2-Fluoro-3-methylphenyl)ethyl]-1H-imidazole

The compound of Example 7 (18 mg, 0.09 mmol) was dissolved inethanol:hexane (1:1, 2 ml) and the enantiomers were separated byautomated preparative liquid chromatography (Gilson system, 250×20 mm IDChiralcel OD-H, 5 μm column, 15 ml/min) using ethanol:hexane [5:95] asthe mobile phase. The appropriate fractions were combined andconcentrated to give the title compound (6 mg). Retention time=6.15 minChiralcel OD-H, 250×4.6 mm ID, 5 μm column, ethanol:hexane [10:90], 1ml/min Rhip. Funct. ED₁₀₀ mg/cm²=0.3

Example 65 2-[(1R*)-1-(2-Fluoro-3-methylphenyl)ethyl]-1H-imidazole

The compound of Example 7 (18 mg, 0.09 mmol) was dissolved inethanol:hexane (1:1, 2 ml) and the enantiomers were separated byautomated preparative liquid chromatography (Gilson system, 250×20 mm IDChiralcel OD-H, 5 μm column, 15 ml/min) using ethanol:hexane [5:95] asthe mobile phase. The appropriate fractions were combined andconcentrated to give the title compound (7 mg).

Retention time=6.90 min Chiralcel OD-H, 250×4.6 mm ID 5 μm column,ethanol:hexane [10:90], 1 ml/min Rhip. Funct. ED₁₀₀ mg/cm²=1

Example 66 {2-[(R*)1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpivalate

To a suspension of the compound of Example 1 (120 mg, 0.6 mmol) andpotassium carbonate (246 mg, 1.8 mmol) in dimethylformamide (4 ml) wasadded chloromethyl pivalate (215 μl, 1.5 mmol) and the reaction mixturestirred at room temperature overnight. Water (10 ml) was added and themixture then extracted with ethyl acetate (2×10 ml). The organic layerswere combined, washed with water (10 ml) and brine (10 ml), dried(MgSO₄) and concentrated in vacuo. The residue was dissolved inacetonitrile (2 ml) and purified by automated preparative liquidchromatography (Gilson system, 150 mm×21.2 mm LUNA C18(2) 5 μm column)using an acetonitrile:water gradient [50:50 to 95:5]. The appropriatefractions were concentrated in vacuo to give the title compound (136mg).

Experimental MH⁺ 315.4; expected 315.2 ¹H-NMR (CD₃OD): 0.96-0.99 (9H),1.58-1.61 (3H), 2.28-2.30 (3H), 2.35-2.38 (3H), 4.62-4.72 (1H),5.53-5.66 (2H), 6.60-6.64 (1H), 6.90-7.00 (3H), 7.18-7.19 (1H) Rhip.Funct. ED₁₀₀ mg/cm²=0.03

Example 67 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpropionate

To a suspension of the compound of Example 1 (120 mg, 0.6 mmol) andcaesium carbonate (731 mg, 1.8 mmol) in acetone (4 ml), under nitrogen,was added chloromethyl propionate (Eur. J. Pharm. Sci: 24; 5; 2005;433-440, 183 mg, 1.5 mmol) and the reaction mixture was stirred at roomtemperature for 18 h. The mixture was filtered and the filtrate wasconcentrated in vacuo.

The residue was dissolved in acetonitrile (1.5 ml) and purified byautomated preparative liquid chromatography (Gilson system, 150 mm×21.2mm LUNA C18(2) 5 mm column) using an acetonitrile:water gradient [50:50to 95:5]. The appropriate fractions were concentrated to give the titlecompound (137 mg).

Experimental MH⁺ 287.4; expected 287.2 ¹H-NMR (CD₃OD): 0.84-0.11 (3H),1.53-1.59 (3H), 1.82-2.02 (2H), 2.22-2.30 (3H), 2.31-2.38 (3H),4.60-4.68 (1H), 5.41-5.48 (1H), 5.64-5.69 (1H), 6.50-6.56 (1H),6.83-6.99 (3H), 7.13-7.16 (1H) Rhip. Funct. ED₁₀₀ mg/cm²=0.01

Similarly prepared from Example 1 were:

MH⁺ Rhip. Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor From Expected mg/cm²68

Chloromethyl 3-methyl- butanoate Ref. 1 315.5 315.2 0.03 69

Chloromethyl heptanoate Prep. 117 343.5 343.2 0.03 70

Chloromethyl butyrate — 301.5 301.2 0.01 71

Chloromethyl 3- cyclopentylpropanoate Prep. 116 355.6 355.3 <=0.03 72

Chloromethyl pentanoate Ref. 2 315.4 315.2 0.03 73

Chloromethyl 3,3- dimethylbutanoate Prep. 118 329.4 329.2 0.01 74

Chloromethyl 2-methyl- propanoate Ref. 3 301.6 301.3 <0.03 <=0.1 Ref. 1:Acta Chem. Scand. Ser. B; EN; 36; 7; 1982; 467-474. Ref. 2: J. Am. Chem.Soc.; 43; 1921; 665 Ref. 3: EP-79782, Example 6

Example 68 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl3-methyl butanoate

¹H-NMR (CD₃OD): 0.75-0.80 (6H), 1.54-1.58 (3H), 1.70-1.80 (1H),1.80-1.84 (2H), 2.23-2.30 (3H), 2.31-2.34 (3H), 4.60-4.68 (1H),5.48-5.55 (1H), 5.61-5.68 (1H), 6.51-6.58 (1H), 6.83-6.95 (2H),6.95-6.99 (1H), 7.12-7.18 (1H)

Example 69 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylheptanoate

¹H-NMR (CD₃OD): 0.82-0.89 (3H), 1.08-1.3 (6H), 1.3-1.4 (2H), 1.52-1.59(3H), 1.88-1.98 (2H), 2.24-2.30 (3H), 2.30-2.35 (3H), 4.60-4.69 (1H),5.42-5.51 (1H), 5.62-5.71 (1H), 6.50-6.56 (1H), 6.86-6.99 (3H),7.12-7.16 (1H)

Example 70 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylbutyrate

¹H-NMR (CD₃OD): 0.78-0.83 (3H), 1.35-1.47 (2H), 1.55-1.61 (3H),1.90-1.98 (2H), 2.28-2.32 (3H), 2.33-2.37 (3H), 4.61-4.70 (1H),5.48-5.55 (1H), 5.64-5.72 (1H), 6.53-6.59 (1H), 6.90-6.96 (2H),6.97-7.01 (1H), 7.16-7.20 (1H)

Example 71 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl3-cyclopentylpropanoate

¹H-NMR (CD₃OD): 0.92-1.06 (2H), 1.35-1.45 (2H), 1.47-1.55 (2H),1.56-1.63 (6H), 1.63-1.73 (2H), 1.91-2.00 (2H), 2.28-2.33 (3H),2.33-2.38 (3H), 4.62-4.71 (1H), 5.48-5.55 (1H), 5.68-5.73 (1H),6.52-6.59 (1H), 6.88-7.01 (3H), 7.18-7.19 (1H)

Example 72 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpentanoate

¹H-NMR (CD₃OD): 0.82-0.86 (3H), 1.13-1.24 (2H), 1.31-1.40 (2H),1.56-1.61 (3H), 1.87-2.00 (2H), 2.26-2.31 (3H), 2.32-2.36 (2H),4.61-4.69 (1H), 5.46-5.52 (1H), 5.66-5.72 (1H), 6.52-6.58 (1H),6.88-7.00 (3H), 7.15-7.17 (1H)

Example 73 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl3,3-dimethylbutanoate

¹H-NMR (d₆-Acetone): 0.89-0.92 (9H), 1.58-1.60 (3H), 1.96-1.97 (2H),2.29-2.31 (3H), 2.38-2.40 (3H), 4.60-4.64 (1H), 5.50-5.54 (1H),5.70-5.74 (1H), 6.67-6.69 (1H), 6.90-6.96 (2H), 6.99-7.01 (1H),7.12-7.14 (1H)

Example 74 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl2-methylpropanoate

¹H-NMR (d₆-Acetone): 0.91-0.94 (6H), 1.58-1.60 (3H), 2.20-2.24 (1H),2.24-2.26 (3H), 2.36-2.38 (3H), 4.60-4.64 (1H), 5.66-5.70 (1H),5.68-5.70 (1H), 6.90-6.95 (2H), 6.98-7.00 (1H), 7.12-7.14 (1H)

Similarly prepared from Example 58 was:

MH⁺ Rhip. Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor From Expected mg/cm²75

Chloromethyl propionate Ref. 4 287.2 287.2 <=0.03, <=0.01, 0.3

Example 75 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpropionate

¹H-NMR (d₆-Acetone): 0.89-0.95 (3H), 1.57-1.60 (3H), 2.03-2.06 (2H),2.27-2.29 (3H), 2.32-2.35 (3H), 4.60-4.65 (1H), 5.44-5.50 (1H),5.71-5.76 (1H), 6.62-6.64 (1H), 6.90-7.00 (3H), 7.14-7.16 (1H)

Example 76 1-Benzyl-2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

To a suspension of the compound of Example 1 (100 mg, 0.50 mmol) andcaesium carbonate (407 mg, 1.25 mmol) in acetone (4 ml) was added benzylbromide (171 mg, 1.00 mmol). The reaction mixture was stirred at roomtemperature, under nitrogen, for 18 h and then concentrated in vacuo.The residue was partitioned between water (10 ml) and ethyl acetate (10ml) and the two layers were separated. The aqueous layer was extractedwith ethyl acetate (10 ml) and the combined organic phases were dried(MgSO₄) and concentrated in vacuo.

The residue was dissolved in methanol:water (9:1, 2 ml) and purified byautomated preparative liquid chromatography (Gilson system, 150 mm×30 mmLUNA C18(2) 10 μm column, 40 ml/min) using an acetonitrile:watergradient [60:40 to 95:5]. The appropriate fractions were concentrated invacuo to give the title compound (100 mg).

Experimental MH⁺ 291.0; expected 291.2 ¹H-NMR (d₆-Acetone): 1.45-1.55(3H), 2.15-2.20 (3H), 2.20-2.24 (3H), 4.26-4.35 (1H), 4.65-4.70 (1H),4.85-4.93 (1H), 6.66-6.70 (1H), 6.82-7.00 (6H), 7.17-7.28 (3H)

Rhip. Funct. ED₁₀₀ mg/cm²=0.01

Similarly prepared from Example 1 were:

Precursor MH⁺ Rhip. Funct. Ex. (all commercially Found/ ED₁₀₀ No. R⁶available) Expected mg/cm² 77

1-(Bromomethyl)-3- methoxybenzene 321.4 321.2 >1 78

(1-Bromoethyl)benzene 305.4 305.2 >1

Example 772-[1-(2,3-Dimethylphenyl)ethyl]-1-(3-methoxybenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.50-1.56 (3H), 2.19-2.28 (6H), 3.66-3.72 (3H),4.30-4.39 (1H), 4.66-4.71 (1H), 4.86-4.94 (1H), 6.40-6.44 (1H),6.48-6.52 (1H), 6.71-6.80 (2H), 6.90-6.99 (3H), 7.00-7.02 (1H),7.14-7.20 (1H)

Example 782-[1-(2,3-Dimethylphenyl)ethyl]-1-(1-phenylethyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.72-1.79 (3H), 1.80-1.90 (3H), 2.23-2.31 (6H),5.05-5.11 (1H), 5.48-5.58 (1H), 6.64-6.70 (1H), 6.70-6.80 (2H),6.88-6.95 (1H), 6.95-7.00 (1H), 7.04-7.20 (4H), 7.66-7.70 (1H)

Example 79 1-[4-({2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)phenyl]-1H-1,2,4-triazole

To a mixture of the compound of Example 58 (90 mg, 0.45 mmol) andcaesium carbonate (244 mg, 0.75 mmol) in 1-methyl-2-pyrrolidinone (1 ml)was added 1-[4-(bromomethyl)phenyl]-1H-1,2,4-triazole (83 μl, 0.5 mmol).The reaction mixture was stirred at room temperature for 18 h and thenconcentrated in vacuo. The residue was dissolved in1-methyl-2-pyrrolidinone (0.8 ml) and purified by automated preparativeliquid chromatography (Gilson system, 150 mm×22.4 mm LUNA C18(2) 5 μmcolumn, 20 ml/min) using an acetonitrile:water gradient [15:85 (3 min)to 98:2 (11 min)]. The appropriate fractions were combined andconcentrated to give the title compound (57 mg).

Experimental MH⁺ 358.5; expected 358.2 ¹H-NMR (CDCl₃): 1.61-1.66 (3H),2.13-2.21 (6H), 4.20-4.26 (1H), 4.60-4.80 (2H), 6.63-6.66 (1H),6.80-6.82 (1H), 6.87-6.98 (4H), 7.11-7.13 (1H), 7.47-7.51 (2H),8.04-8.06 (1H), 8.43-8.45 (1H) Rhip. Funct. ED₁₀₀ mg/cm²<=10

Example 801-[3-(Benzyloxy)benzyl]-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

To a mixture of the compound of Example 58 (90 mg, 0.45 mmol) andcaesium carbonate (244 mg, 0.75 mmol) in 1-methyl-2-pyrrolidinone (1 ml)was added 1-(benzyloxy)-3-(bromomethyl)benzene (139 mg, 0.50 mmol). Thereaction mixture was stirred at room temperature for 48 h and thenfiltered through a Whatman PTFE filter tube (5 μm).

The filtrate was purified by automated preparative liquid chromatography(Gilson system, 150 mm×22.4 mm LUNA C18(2) 5 μm column, 20 ml/min) usingan acetonitrile:water gradient [50:50 (15 min) to 98:2 (20 min)]. Theappropriate fractions were combined and concentrated to give the titlecompound (31 mg).

Experimental MH⁺ 397.5; expected 397.2 ¹H-NMR (d₆-Acetone): 1.50-1.54(3H), 2.19-2.25 (6H), 4.33-4.38 (1H), 4.65-4.70 (1H), 4.90-4.95 (1H),4.98-5.00 (2H), 6.46-6.51 (2H), 6.74-6.76 (1H), 6.84-6.98 (4H),7.00-7.01 (1H), 7.15-7.20 (1H), 7.31-7.42 (5H) Rhip. Funct. ED₁₀₀mg/cm²<=10

Similarly prepared from Example 58 were:

MH⁺ Rhip. Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor Expected mg/cm² 81

1-(Bromomethyl)-4-(methyl- sulfonyl)benzene 369.4 369.2 1 82

[4-(Bromomethyl)phenyl] (phenyl)methanone 395.4 395.2 <=10 83

Methyl 4-(bromomethyl)- benzoate 349.4 349.2 <=10 84

4-(Bromomethyl)pyridine 292.4 292.2 <=10 85

3-(Bromomethyl)benzonitrile 316.4 316.2 >0.01 86

2-(Bromomethyl)benzonitrile 316.4 316.2 >0.01 87

3-(Bromomethyl)-4-fluoro- benzonitrile 334.4 334.2 >0.01 88

1-(Bromomethyl)-3,5-dimethoxy- benzene 351.5 351.2 >0.01 89

1-(Bromomethyl)-4-methoxy- benzene 321.4 321.2 >0.01 90

1-(Bromomethyl)-3-methoxy- benzene 321.4 321.2 >0.01 91

Methyl 4-(bromomethyl)-3- methoxybenzoate 379.5 379.2 >0.01 92

1-[4-(Bromomethyl)phenyl]-1H- pyrazole 357.5 357.2 >0.01 93

1-(Bromomethyl)-4-fluoro- benzene 309.4 309.2 <=10 94

4-(Bromomethyl)-1,2-difluoro- benzene 327.2 327.2 >0.01 95

1-(Bromomethyl)-2-fluoro- benzene 309.3 309.2 >0.01 96

1-(Bromomethyl)-3- (difluoromethoxy)benzene 357.2 357.2 <=10 97

1-(Bromomethyl)-2,3-difluoro- benzene 327.2 327.2 >0.01 98

1-(Bromomethyl)-3-fluoro- benzene 309.3 309.2 >0.01 99

1-(Bromomethyl)-2,4-difluoro- benzene 327.4 327.2 >0.01 100

1-(Bromomethyl)-3,5-difluoro- benzene 327.4 327.2 >0.01 101

2-(Bromomethyl)-1,3-difluoro- benzene 327.4 327.2 >0.01 102

1-(Bromomethyl)-2-chloro-4- fluorobenzene 343.4 343.1 >0.01 103

2-(Bromomethyl)-1,4-difluoro- benzene 327.4 327.2 >0.01 104

1-(Bromomethyl)-4-chloro-2- fluorobenzene 343.4 343.1 >0.01 105

2-(Bromomethyl)-1,3,4-trifluoro- benzene 345.4 345.2 >0.01 106

1-(Bromomethyl)-2,4,5-trifluoro- benzene 345.5 345.2 >0.01 107

1-(Bromomethyl)-4-methyl- benzene 305.5 305.2 <=10 108

2-(Bromomethyl)-1,3,5-trifluoro- benzene 345.4 345.2 >0.01 109

1-(Bromomethyl)-2-methyl- benzene 305.4 305.2 <=10 110

1-(Bromomethyl)-4-fluoro-2- (trifluoromethyl)benzene 377.5377.2 >0.01, >0.03 111

1-(Bromomethyl)-2-fluoro-3- methylbenzene 323.2 323.2 >0.01, >0.03 112

1-(Bromomethyl)-3- (trifluoromethyl)benzene 359.2 359.2 <=10 113

1-(Bromomethyl)-4-chloro- benzene 325.1 325.1 <=10 114

1-(Bromomethyl)-4- (trifluoromethyl)benzene 359.2 359.2 <=10 115

1-(Bromomethyl)-3-chloro- benzene 325.1 325.1 >0.01 116

1-(Bromomethyl)-2- (trifluoromethyl)benzene 359.2 359.2 >0.01 117

4-(Bromomethyl)-2-fluoro-1- (trifluoromethyl)benzene 377.2 377.2 <=10118

2-(Bromomethyl)-4-fluoro-1- (trifluoromethyl)benzene 377.2 377.2 <=10119

1-(Bromomethyl)-3-chloro-2- fluorobenzene 343.2 343.1 <=10 120

1-(Bromomethyl)-3,5-dimethyl- benzene 319.4 319.2 <=10 121

1-(Bromomethyl)-2-ethyl- benzene No mass ion <=10 122

1-(Bromomethyl)-2- (trifluoromethoxy)benzene 375.4 375.2 <=10 123

1-(Bromomethyl)-3- (trifluoromethoxy)benzene 375.4 375.2 >0.1 124

4′-(Bromomethyl)biphenyl-2- carbonitrile 392.5 392.2 >0.1 125

1-(Bromomethyl)-4-iodobenzene 417.3 417.1 >0.1 126

1-(Bromomethyl)-4- [(trifluoromethyl)thio]benzene 391.4 391.1 <=10 127

1-(Bromomethyl)-3-(4-fluoro- phenoxy)benzene 401.4 401.2 >0.1 128

1-(Bromomethyl)-4-tert-butyl- benzene 347.5 347.2 <=10 129

2-(Bromomethyl)-1,4-dichloro- benzene 359.4 359.1 <=10 130

2-(Bromomethyl)-1-chloro-4- (trifluoromethyl)benzene 393.4 393.1 1 131

2-(Bromomethyl)-4-chloro-1- methylbenzene 339.4 339.2 1 132

2-(Bromomethyl)naphthalene 341.4 341.2 <=10 133

4-(Bromomethyl)-1,2-dichloro- benzene 359.4 359.1 <=10 134

2-(Bromomethyl)-1,3-dichloro- benzene 359.4 359.1 >0.1 135

4-(Bromomethyl)biphenyl 367.4 367.2 >0.1

Example 812-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-[4-(methylsulfonyl)benzyl]-1H-imidazole

¹H-NMR (CDCl₃): 1.60-1.64 (3H), 2.09-2.11 (3H), 2.18-2.20 (3H),2.97-3.00 (3H), 4.19-4.23 (1H), 4.70-4.76 (1H), 4.79-4.85 (1H),6.61-6.65 (1H), 6.80-6.81 (1H), 6.84-6.95 (4H), 7.14-7.17 (1H),7.72-7.78 (2H)

Example 82[4-({2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)phenyl](phenyl)methanone

¹H-NMR (CDCl₃): 1.64-1.70 (3H), 2.17-2.19 (3H), 2.22-2.24 (3H),4.23-4.29 (1H), 4.70-4.77 (1H), 4.80-4.86 (1H), 6.80-6.84 (1H),6.85-6.92 (3H), 6.94-7.00 (2H), 7.18-7.20 (1H), 7.45-7.52 (2H),7.59-7.62 (1H), 7.68-7.72 (2H), 7.75-7.79 (2H)

Example 83 Methyl4-({2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)benzoate

¹H-NMR (d₆-Acetone): 1.53-1.61 (3H), 2.15-2.22 (6H), 3.83-3.85 (3H),4.28-4.35 (1H), 4.80-4.86 (1H), 5.02-5.10 (1H), 6.70-6.74 (1H),6.86-6.98 (5H), 7.05-7.07 (1H), 7.80-7.84 (2H)

Example 844-({2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)pyridine

¹H-NMR (CDCl₃): 1.61-1.64 (3H), 2.10-2.12 (3H), 2.21-2.23 (3H),4.12-4.20 (1H), 4.60-4.66 (1H), 4.75-4.80 (1H), 6.65-6.71 (3H),6.82-6.83 (1H), 6.89-6.96 (2H), 7.12-7.13 (1H), 8.40-8.44 (2H)

Example 853-({2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)benzonitrile

¹H-NMR (d₆-Acetone): 1.55-1.58 (3H), 2.17-2.20 (6H), 4.38-4.41 (1H),4.93-4.98 (1H), 5.05-5.09 (1H), 6.63-6.65 (1H), 6.80-6.87 (2H),6.97-7.00 (2H), 7.12-7.13 (1H), 7.18-7.20 (1H), 7.37-7.40 (1H),7.52-7.54 (1H)

Example 862-({2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)benzonitrile

¹H-NMR (d₆-Acetone): 1.55-1.58 (3H), 2.16-2.20 (6H), 4.29-4.33 (1H),4.93-4.98 (1H), 5.10-5.14 (1H), 6.66-6.68 (1H), 6.80-6.86 (2H),6.95-7.00 (3H), 7.10-7.11 (1H), 7.57-7.59 (2H)

Example 873-({2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)-4-fluorobenzonitrile

¹H-NMR (d₆-Acetone): 1.57-1.60 (3H), 2.16-2.18 (3H), 2.20-2.22 (3H),4.42-4.46 (1H), 5.01-5.05 (1H), 5.06-5.11 (1H), 6.60-6.68 (2H),6.80-6.82 (2H), 7.00-7.01 (1H), 7.15-7.16 (1H), 7.21-7.25 (1H),7.60-7.62 (1H)

Example 881-(3,5-Dimethoxybenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.20-2.25 (6H), 3.62-3.66 (6H),4.33-4.38 (1H), 4.60-4.64 (1H), 4.81-4.85 (1H), 6.02-6.05 (2H),6.36-6.38 (1H), 6.76-6.79 (1H), 6.90-6.98 (3H), 7.00-7.01 (1H)

Example 892-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(4-methoxybenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.20-2.25 (6H), 3.76-3.78 (3H),4.36-4.40 (1H), 4.60-4.64 (1H), 4.80-4.84 (1H), 6.68-6.70 (1H),6.79-6.85 (4H), 6.90-7.00 (4H)

Example 902-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(3-methoxybenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.20-2.25 (6H), 3.65-3.67 (3H),4.36-4.40 (1H), 4.62-4.66 (1H), 4.90-4.94 (1H), 6.40-6.42 (1H),6.48-6.50 (1H), 6.72-6.74 (1H), 6.79-6.81 (1H), 6.95-7.00 (3H),7.00-7.01 (1H), 7.17-7.20 (1H)

Example 91 Methyl4-({2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)-3-methoxybenzoate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.16-2.18 (3H), 2.20-2.22 (3H),3.84-3.90 (6H), 4.32-4.36 (1H), 4.81-4.86 (2H), 6.46-6.48 (1H),6.71-6.73 (1H), 6.85-6.90 (2H), 6.97-6.98 (1H), 7.01-7.02 (1H),7.39-7.41 (1H), 7.50-7.51 (1H)

Example 92 1-[4-({2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)phenyl]-1H-pyrazole

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.20-2.24 (6H), 4.36-4.40 (1H),4.78-4.82 (1H), 4.96-5.00 (1H), 6.44-6.46 (1H), 6.70-6.72 (1H),6.90-7.00 (5H), 7.04-7.06 (1H), 7.63-7.69 (3H), 8.21-8.23 (1H)

Example 932-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(4-fluorobenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.53-1.56 (3H), 2.19-2.24 (6H), 4.32-4.36 (1H),4.71-4.75 (1H), 4.90-4.94 (1H), 6.65-6.67 (1H), 6.89-6.95 (3H),6.95-7.00 (4H), 7.00-7.01 (1H)

Example 941-(3,4-Difluorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.55-1.58 (3H), 2.20-2.23 (6H), 4.36-4.40 (1H),4.80-4.84 (1H), 4.97-5.01 (1H), 6.62-6.70 (3H), 6.82-6.90 (2H),6.96-6.98 (1H), 7.04-7.05 (1H), 7.06-7.10 (1H)

Example 952-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(2-fluorobenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.59 (3H), 2.20-2.24 (6H), 4.38-4.42 (1H),4.80-4.90 (2H), 6.60-6.63 (1H), 6.64-6.66 (1H), 6.88-6.95 (3H),7.00-7.03 (2H), 7.06-7.09 (1H), 7.25-7.28 (1H)

Example 961-[3-(Difluoromethoxy)benzyl]-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.19-2.23 (6H), 4.32-4.38 (1H),4.79-4.83 (1H), 4.97-5.01 (1H), 6.61-6.63 (1H), 6.70-6.79 (2H),6.81-6.82 (1H), 6.88-6.99 (2H), 7.00-7.05 (2H), 7.25-7.30 (1H)

Example 971-(2,3-Difluorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.59 (3H), 2.20-2.24 (6H), 4.39-4.43 (1H),4.89-4.93 (1H), 5.00-5.04 (1H), 6.39-6.41 (1H), 6.61-6.63 (1H),6.81-6.90 (2H), 6.95-7.00 (2H), 7.06-7.07 (1H), 7.14-7.19 (1H)

Example 982-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(3-fluorobenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.19-2.23 (6H), 4.32-4.36 (1H),4.76-4.80 (1H), 4.96-5.00 (1H), 6.53-6.55 (1H), 6.70-6.75 (2H),6.89-6.99 (4H), 7.02-7.04 (1H), 7.22-7.25 (1H)

Example 991-(2,4-Difluorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.59 (3H), 2.20-2.24 (6H), 4.39-4.43 (1H),4.81-4.91 (2H), 6.60-6.65 (2H), 6.77-6.80 (1H), 6.83-6.86 (1H),6.89-6.99 (3H), 7.01-7.03 (1H)

Example 1001-(3,5-Difluorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.59 (3H), 2.19-2.23 (6H), 4.36-4.40 (1H),4.81-4.85 (1H), 5.00-5.04 (1H), 6.40-6.44 (2H), 6.69-6.71 (1H),6.78-6.82 (1H), 6.83-6.90 (2H), 6.98-6.99 (1H), 7.09-7.10 (1H)

Example 1011-(2,6-Difluorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.57-1.60 (3H), 2.26-2.28 (3H), 2.37-2.39 (3H),4.60-4.64 (1H), 4.72-4.77 (1H), 5.05-5.10 (1H), 6.57-6.59 (1H),6.85-6.84 (3H), 6.97-7.05 (3H), 7.39-7.43 (1H)

Example 1021-(2-Chloro-4-fluorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.59 (3H), 2.16-2.20 (6H), 4.32-4.37 (1H),4.81-4.85 (1H), 4.96-5.00 (1H), 6.29-6.32 (1H), 6.69-6.71 (1H),6.82-6.88 (3H), 6.99-7.03 (2H), 7.20-7.22 (1H)

Example 1031-(2,5-Difluorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.57-1.60 (3H), 2.19-2.24 (6H), 4.40-4.44 (1H),4.87-4.91 (1H), 4.96-5.00 (1H), 6.16-6.20 (1H), 6.67-6.70 (1H),6.82-6.88 (2H), 6.96-7.00 (2H), 7.06-7.09 (2H)

Example 1041-(4-Chloro-2-fluorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.59 (3H), 2.19-2.23 (6H), 4.39-4.44 (1H),4.82-4.86 (1H), 4.96-5.00 (1H), 6.49-6.53 (1H), 6.65-6.68 (1H),6.80-6.90 (2H), 6.96-6.99 (2H), 7.07-7.08 (1H), 7.16-7.19 (1H)

Example 1052-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(2,3,6-trifluorobenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.57-1.60 (3H), 2.21-2.23 (3H), 2.36-2.38 (3H),4.57-4.61 (1H), 4.85-4.89 (1H), 4.97-5.01 (1H), 6.47-6.50 (1H),6.81-6.89 (2H), 6.90-7.01 (3H), 7.23-7.28 (1H)

Example 1062-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(2,4,5-trifluorobenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.57-1.60 (3H), 2.18-2.20 (3H), 2.21-2.23 (3H),4.40-4.45 (1H), 4.90-4.94 (1H), 4.95-5.01 (1H), 6.27-6.32 (1H),6.61-6.63 (1H), 6.80-6.88 (2H), 6.99-7.00 (1H), 7.10-7.11 (1H),7.11-7.15 (1H)

Example 1072-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(4-methylbenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.51-1.55 (3H), 2.20-2.22 (3H), 2.22-2.26 (6H),4.30-4.36 (1H), 4.61-4.65 (1H), 4.80-4.85 (1H), 6.70-6.72 (1H),6.78-6.81 (2H), 6.90-6.99 (4H), 7.03-7.06 (2H)

Example 1082-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(2,4,6-trifluorobenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.57-1.60 (3H), 2.21-2.23 (3H), 2.30-2.32 (3H),4.57-4.61 (1H), 4.76-4.80 (1H), 4.84-4.88 (1H), 6.47-6.49 (1H),6.81-6.92 (5H), 6.97-6.99 (1H)

Example 1092-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(2-methylbenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.55-1.58 (3H), 2.02-2.04 (3H), 2.10-2.12 (3H),2.21-2.23 (3H), 4.21-4.36 (1H), 4.65-4.69 (1H), 4.78-4.82 (1H),6.47-6.49 (1H), 6.75-6.77 (1H), 6.80-6.82 (1H), 6.95-7.00 (3H),7.04-7.07 (1H), 7.18-7.20 (2H)

Example 1102-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-[4-fluoro-2-(trifluoromethyl)benzyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.57-1.60 (3H), 2.07-2.09 (3H), 2.15-2.17 (3H),4.28-4.32 (1H), 5.00-5.04 (1H), 5.16-5.20 (1H), 6.38-6.41 (1H),6.78-6.80 (1H), 6.85-6.88 (2H), 7.00-7.04 (2H), 7.16-7.19 (1H),7.41-7.43 (1H)

Example 1112-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(2-fluoro-3-methylbenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.57-1.59 (3H), 2.20-2.25 (9H), 4.38-4.42 (1H),4.80-4.86 (2H), 6.44-6.48 (1H), 6.64-6.66 (1H), 6.87-6.97 (4H),7.00-7.01 (1H), 7.10-7.14 (1H)

Example 1122-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-[3-(trifluoromethyl)benzyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.52-1.56 (3H), 2.18-2.21 (6H), 4.36-4.40 (1H),4.90-4.95 (1H), 5.08-5.12 (1H), 6.67-6.70 (1H), 6.81-6.90 (2H),6.98-6.99 (1H), 7.10-7.16 (3H), 7.40-7.44 (1H), 7.50-7.52 (1H)

Example 1131′-(4-Chlorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.18-2.22 (6H), 4.31-4.38 (1H),4.86-4.91 (1H), 4.95-4.99 (1H), 6.67-6.70 (1H), 6.81-6.97 (5H),7.03-7.04 (1H), 7.20-7.23 (1H)

Example 1142-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-[4-(trifluoromethyl)benzyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.52-1.56 (3H), 2.17-2.20 (6H), 4.31-4.39 (1H),4.90-4.96 (1H), 5.07-5.12 (1H), 6.67-6.70 (1H), 6.83-6.89 (2H),6.99-7.04 (3H), 7.09-7.10 (1H), 7.49-7.53 (2H)

Example 1151′-(3-Chlorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.58 (3H), 2.00-2.05 (6H), 4.34-4.39 (1H),4.78-4.82 (1H), 4.98-5.02 (1H), 6.69-6.71 (1H), 6.79-6.83 (2H),6.87-6.97 (3H), 7.04-7.05 (1H), 7.19-7.23 (2H)

Example 1162-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-[2-(trifluoromethyl)benzyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.58 (3H), 2.01-2.03 (3H), 2.16-2.18 (3H),4.22-4.28 (1H), 4.99-5.03 (1H), 5.15-5.20 (1H), 6.40-6.42 (1H),6.78-6.80 (1H), 6.89-6.92 (2H), 7.01-7.04 (2H), 7.40-7.44 (2H),7.70-7.72 (1H)

Example 1172-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-[3-fluoro-4-(trifluoromethyl)benzyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.54-1.58 (3H), 2.10-2.17 (6H), 4.38-4.42 (1H),5.00-5.05 (1H), 5.12-5.18 (1H), 6.60-6.70 (2H), 6.80-6.85 (3H),7.00-7.01 (1H), 7.16-7.17 (1H), 7.45-7.52 (1H)

Example 1182-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-[5-fluoro-2-(trifluoromethyl)benzyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.57-1.60 (3H), 2.09-2.15 (6H), 4.31-4.38 (1H),5.02-5.07 (1H), 5.10-5.15 (1H), 5.95-5.98 (1H), 6.78-6.80 (1H),6.81-6.88 (2H), 7.04-7.05 (1H), 7.10-7.16 (2H), 7.72-7.76 (1H)

Example 1191-(3-Chloro-2-fluorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.55-1.58 (3H), 2.20-2.23 (6H), 4.39-4.44 (1H),4.90-4.95 (1H), 5.00-5.05 (1H), 6.50-6.54 (1H), 6.61-6.63 (1H),6.80-6.90 (2H), 6.95-7.00 (2H), 7.09-7.10 (1H), 7.30-7.35 (1H)

Example 1201-(3,5-Dimethylbenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.17-2.19 (6H), 2.21-2.25 (6H),4.35-4.40 (1H), 4.60-4.65 (1H), 4.80-4.85 (1H), 6.42-6.45 (2H),6.71-6.73 (1H), 6.81-6.82 (1H), 6.90-7.00 (4H)

Example 1212-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(2-ethylbenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 0.98-1.02 (3H), 1.56-1.59 (3H), 2.16-2.17 (3H),2.21-2.22 (3H), 2.30-2.38 (2H), 4.25-4.34 (1H), 4.71-4.77 (1H),4.80-4.85 (1H), 6.57-6.59 (1H), 6.73-6.80 (2H), 6.94-7.00 (3H),7.05-7.09 (1H), 7.20-7.23 (2H)

Example 1222-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-[2-(trifluoromethoxy)benzyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.55-1.59 (3H), 2.16-2.22 (6H), 4.31-4.38 (1H),4.82-4.87 (1H), 4.99-5.02 (1H), 6.58-6.60 (1H), 6.67-6.70 (1H),6.84-6.91 (2H), 6.97-6.99 (1H), 7.01-7.02 (1H), 7.16-7.20 (1H),7.30-7.40 (2H)

Example 1232-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-[3-(trifluoromethoxy)benzyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.59 (3H), 2.19-2.22 (6H), 4.36-4.40 (1H),4.80-4.85 (1H), 5.00-5.05 (1H), 6.70-6.72 (1H), 6.78-6.80 (1H),6.82-6.94 (3H), 6.99-7.00 (1H), 7.06-7.08 (1H), 7.16-7.19 (1H),7.35-7.38 (1H)

Example 1244′-({2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)biphenyl-2-carbonitrile

¹H-NMR (d₆-Acetone): 1.57-1.60 (3H), 2.20-2.21 (6H), 4.38-4.42 (1H),4.81-4.85 (1H), 5.00-5.05 (1H), 6.76-6.78 (1H), 6.90-7.02 (5H),7.07-7.08 (1H), 7.42-7.45 (2H), 7.58-7.61 (2H), 7.78-7.80 (1H),7.82-7.84 (1H)

Example 1252-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(4-iodobenzyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 1.97-1.99 (3H), 2.00-2.02 (3H),4.30-4.35 (1H), 4.75-4.80 (1H), 4.96-5.00 (1H), 6.61-6.64 (2H),6.68-6.70 (1H), 6.86-6.95 (3H), 7.01-7.02 (1H), 7.58-7.60 (2H)

Example 1262-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-{4-[(trifluoromethyl)thio]benzyl}-1H-imidazole

¹H-NMR (d₆-Acetone): 1.53-1.56 (3H), 2.17-2.20 (6H), 4.31-4.38 (1H),4.83-4.88 (1H), 5.03-5.08 (1H), 6.67-6.69 (1H), 6.82-6.88 (2H),6.95-7.00 (3H), 7.07-7.08 (1H), 7.50-7.54 (2H)

Example 1272-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-[3-(4-fluorophenoxy)benzyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.19-2.23 (6H), 4.33-4.38 (1H),4.67-4.71 (1H), 4.89-4.93 (1H), 6.50-6.52 (1H), 6.64-6.68 (2H),6.80-6.82 (1H), 6.86-7.00 (6H), 7.14-7.19 (2H), 7.22-7.25 (1H)

Example 1281-(4-tert-Butylbenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.13-1.15 (9H), 1.51-1.53 (3H), 2.20-2.26 (6H),4.36-4.40 (1H), 4.66-4.70 (1H), 4.82-4.87 (1H), 6.70-6.73 (1H),6.80-6.82 (2H), 6.90-7.00 (4H), 7.25-7.28 (2H)

Example 1291-(2,5-Dichlorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.55-1.59 (3H), 2.11-2.20 (6H), 4.37-4.41 (1H),4.89-4.93 (1H), 5.02-5.06 (1H), 6.19-6.21 (1H), 6.76-6.79 (1H),6.80-6.82 (1H), 6.82-6.84 (1H), 7.00-7.01 (1H), 7.09-7.10 (1H),7.19-7.22 (1H), 7.37-7.39 (1H)

Example 1301-[2-Chloro-5-(trifluoromethyl)benzyl]-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.60 (3H), 2.10-2.12 (3H), 2.18-2.20 (3H),4.39-4.44 (1H), 4.99-5.05 (1H), 5.12-5.18 (1H), 6.57-6.59 (1H),6.71-6.80 (3H), 7.01-7.03 (1H), 7.10-7.12 (1H), 7.50-7.53 (1H),7.58-7.60 (1H)

Example 1311-(5-Chloro-2-methylbenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.56-1.60 (3H), 2.02-2.04 (3H), 2.10-2.12 (3H),2.20-2.21 (3H), 4.24-4.28 (1H), 4.71-4.78 (1H), 4.88-4.93 (1H),6.32-6.34 (1H), 6.78-6.80 (1H), 6.90-7.00 (4H), 7.13-7.17 (1H)

Example 1322-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(2-naphthylmethyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.17-2.21 (6H), 4.38-4.41 (1H),4.87-4.91 (1H), 5.10-5.14 (1H), 6.74-6.78 (1H), 6.90-6.93 (2H),6.98-6.99 (1H), 7.01-7.08 (2H), 7.28-7.29 (1H), 7.43-7.46 (2H),7.70-7.80 (2H), 7.81-7.84 (1H)

Example 1331-(3,4-Dichlorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.19-2.22 (6H), 4.35-4.40 (1H),4.85-4.90 (1H), 5.00-5.06 (1H), 4.98-5.00 (2H), 6.63-6.66 (1H),6.78-6.80 (1H), 6.81-6.87 (3H), 6.99-7.00 (1H), 7.10-7.11 (1H),7.30-7.33 (1H)

Example 1341-(2,6-Dichlorobenzyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.60-1.63 (3H), 2.30-2.32 (3H), 2.40-2.42 (3H),4.66-4.72 (2H), 5.05-5.09 (1H), 6.41-6.43 (1H), 6.67-6.70 (1H),6.81-6.82 (1H), 6.96-7.01 (2H), 7.40-7.46 (3H)

Example 1351-(Biphenyl-4-ylmethyl)-2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.54-1.56 (3H), 2.20-2.22 (6H), 4.36-4.40 (1H),4.80-4.84 (1H), 4.97-5.00 (1H), 6.71-6.73 (1H), 6.93-6.99 (4H),7.06-7.07 (1H), 7.36-7.37 (1H), 7.42-7.46 (3H), 7.55-7.58 (2H),7.60-7.63 (2H)

Example 136Cyclopropylmethyl{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylcarbonate

To a mixture of the compound of Example 1 (100 mg, 0.50 mmol) andcaesium carbonate (407 mg, 1.25 mmol) in acetone (5 ml) and undernitrogen was added Preparation 119 (205 mg, 1.25 mmol). The reactionmixture was stirred at room temperature for 60 h and then concentratedin vacuo. To the residue was added water (10 ml) and ethyl acetate (20ml) and the two layers were separated. The organic phase was then dried(MgSO₄) and concentrated in vacuo.

The residue was dissolved in acetonitrile (0.8 ml) and purified byautomated preparative liquid chromatography (Gilson system, 150 mm×30 mmLUNA C18(2) 10 μm column, 40 ml/min) using an acetonitrile:watergradient [55:45 (20 min) to 98:2 (20.1 min)]. The appropriate fractionswere combined and concentrated to give the title compound (74 mg).

Experimental MH⁺ 329.4; expected 329.2 ¹H-NMR (d₆-Acetone): 0.20-0.30(2H), 0.50-0.60 (2H), 1.05-1.15 (1H), 1.55-1.60 (3H), 2.30-2.40 (6H),3.80-3.95 (2H), 4.60-4.70 (1H), 5.40-5.45 (1H), 5.70-5.80 (1H),6.65-6.70 (1H), 6.90-6.95 (2H), 6.95-7.00 (1H), 7.17-7.20 (1H) Rhip.Funct. ED₁₀₀ mg/cm²=0.01

Similarly prepared from Example 1 were:

MH⁺ Rhip. Funct. Ex. From Found/ ED₁₀₀ No. R⁶ Precursor Prep. Expectedmg/cm² 137

Chloromethyl 4- methoxybenzyl carbonate 120 395.3, 395.2 0.1 138

Chloromethyl 2,2,2-trifluoroethyl carbonate 124 357.3, 357.1 0.03 139

Chloromethyl 3- methylbutyl carbonate 121 345.4, 345.2 <=0.03 140

Chloromethyl isopropyl carbonate 122 317.3, 317.2 0.01 141

Chloromethyl cyclobutyl carbonate 123 329.4, 329.2 0.03

Example 137 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl4-methoxybenzyl carbonate

¹H-NMR (d₆-Acetone): 1.50-1.60 (3H), 2.25-2.35 (6H), 3.80-3.85 (3H),4.60-4.65 (1H), 4.95-5.10 (2H), 5.40-5.50 (1H), 5.70-5.80 (1H),6.60-6.65 (1H), 6.90-7.00 (5H), 7.15-7.18 (1H), 7.25-7.35 (2H)

Example 138 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl2,2,2-trifluoroethyl carbonate

¹H-NMR (d₆-Acetone): 1.50-1.60 (3H), 2.20-2.30 (6H), 4.50-4.70 (3H),5.50-5.55 (1H), 5.80-5.85 (1H), 6.60-6.64 (1H), 6.85-7.00 (3H),7.14-7.18 (1H)

Example 139 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl3-methyl butyl carbonate

¹H-NMR (d₆-Acetone): 0.80-0.90 (6H), 1.40-1.50 (2H), 1.55-1.60 (3H),1.60-1.65 (1H), 2.20-2.30 (6H), 4.00-4.10 (2H), 4.60-4.65 (1H),5.40-5.45 (1H), 5.70-5.75 (1H), 6.60-6.65 (1H), 6.85-6.90 (2H),6.95-7.00 (1H), 7.10-7.15 (1H)

Example 140 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylisopropyl carbonate

¹H-NMR (d₆-Acetone): 1.10-1.20 (6H), 1.50-1.60 (3H), 2.20-2.30 (6H),4.60-4.65 (1H), 4.70-4.75 (1H), 5.38-5.42 (1H), 5.65-5.70 (1H),6.60-6.64 (1H), 6.85-6.90 (2H), 6.95-7.00 (1H), 7.10-7.14 (1H)

Example 141Cyclobutyl{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylcarbonate

¹H-NMR (d₆-Acetone): 1.50-1.60 (3H), 1.60-1.75 (2H), 1.90-2.00 (2H),2.20-2.24 (2H), 2.25-2.30 (6H), 4.55-4.60 (1H), 4.70-4.80 (1H),5.38-5.41 (1H), 5.65-5.70 (1H), 6.60-6.64 (1H), 6.85-6.90 (2H),6.95-7.00 (1H), 7.10-7.13 (1H)

Example 142 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl(2,4-dichlorobenzyl)carbamate

To a mixture of the compound of Example 1 (100 mg, 0.5 mmol) and caesiumcarbonate (163 mg, 0.5 mmol) in anhydrous acetone (2 ml) was addeddropwise the compound of Preparation 125 (134 mg, 0.5 mmol) in anhydrousacetone (1 ml). The reaction mixture was stirred at room temperature for4 days and then ethyl acetate (5 ml) and water (5 ml) was added. The twolayers were separated and the aqueous layer was extracted with ethylacetate (2×5 ml). The combined organic layers were dried (MgSO₄) andconcentrated in vacuo.

The residue was dissolved in methanol (1.5 ml) and purified by automatedpreparative liquid chromatography (Gilson system, 150 mm×30 mm LUNAC18(2) 10 μm column, 40 ml/min) using an acetonitrile:water gradient[55:45 (20 min) to 95:5 (21 min)]. The appropriate fractions werecombined and concentrated to give the title compound (106 mg).

Experimental MH⁺ 432.3; expected 432.1 ¹H-NMR (d₆-Acetone): 1.48-1.55(3H), 2.23-2.27 (3H), 2.29-2.33 (3H), 4.22-4.30 (2H), 4.60-4.65 (1H),5.38-5.41 (1H), 5.59-5.62 (1H), 6.60-6.63 (1H), 6.81-6.95 (3H),7.08-7.10 (1H), 7.20-7.26 (1H), 7.41-7.50 (1H) Rhip. Funct. ED₁₀₀mg/cm²=1

Example 143 1-{2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}ethylmethyl[2-(methylsulfonyl)ethyl]carbamate

To a mixture of the compound of Example 1 (100 mg, 0.5 mmol) and caesiumcarbonate (163 mg, 0.5 mmol) in anhydrous acetone (2 ml) was addeddropwise Preparation 133 (230 mg, 0.5 mmol) in anhydrous acetone (1 ml).The reaction mixture was stirred at room temperature for 14 days andthen dichloromethane (5 ml) and water (5 ml) was added. The two layerswere separated and the aqueous layer was extracted with dichloromethane(2×5 ml). The combined organic layers were dried (MgSO₄) andconcentrated in vacuo.

The residue was dissolved in methanol (1.5 ml) and purified by automatedpreparative liquid chromatography (Gilson system, 150 mm×21.4 mm LUNAC18(2) 5 μm column, 20 ml/min) using an acetonitrile:water gradient[20:80 (3 min) to 98:2 (16 min)]. The appropriate fractions werecombined and concentrated to give the title compound (7 mg).

Experimental MH⁺ 408.4; expected 408.2Rhip. Funct. ED₁₀₀ mg/cm²=0.3

Similarly prepared from Example 1 were:

MH⁺ Rhip. Funct. Ex. From Found/ ED₁₀₀ No. R⁶ Precursor Prep. Expectedmg/cm² 144

1-Chloroethyl morpholine-4- carboxylate 134 358.5 358.2 <=10 145

Chloromethyl thiomorpholine-4- carboxylate 1,1-dioxide 126 392.4 392.2<=10 146

1-(Chloromethyl) 2-methyl (2S)- pyrrolidine-1,2-dicarboxylate 127 386.4386.2 >1 147

Chloromethyl cyclohexylcarbamate 128 356.4 356.2 <=10 148

Chloromethyl [2-(2,4-dichloro- phenyl)ethyl]carbamate 129 446.3 446.1 >1149

Chloromethyl cyclohexyl(methyl)- carbamate 130 370.5 370.2 <=10 150

Chloromethyl benzyl(methyl)- carbamate 131 378.5 378.2 <=10 151

Chloromethyl methyl(2-phenyl- ethyl)carbamate 132 392.5 392.2 <=10 152

1-(1-Chloroethyl) 2-methyl (2S)- pyrrolidine-1,2-dicarboxylate 135 400.4400.2 >1

Example 144 1-{2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}ethylmorpholine-4-carboxylate

¹H-NMR (CD₃OD): 1.06-1.09 (3H), 1.58-1.60 (3H), 2.30-2.31 (3H),2.40-2.41 (2H), 3.39-3.46 (4H), 3.50-3.43 (4H), 4.88-4.92 (1H),6.17-6.20 (1H), 6.38-6.40 (1H), 6.89-6.92 (1H), 6.99-7.01 (1H),7.23-7.24 (1H)

Example 145 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylthiomorpholine-4-carboxylate 1,1-dioxide

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.25-2.27 (3H), 2.37-2.39 (3H),2.75-2.85 (2H), 2.90-3.00 (2H), 3.35-3.42 (2H), 3.76-3.80 (2H),4.61-4.65 (1H), 5.68-5.69 (2H), 6.62-6.64 (1H), 6.89-6.95 (2H),6.98-7.01 (1H), 7.09-7.10 (1H)

Example 146 1-({2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl)2-methyl (2S)-pyrrolidine-1,2-dicarboxylate

¹H-NMR (d₆-Acetone): 1.50-1.55 (3H), 1.78-1.89 (3H), 2.10-2.20 (1H),2.22-2.27 (3H), 2.34-2.39 (3H), 3.58-3.63 (3H), 4.59-4.64 (1H),6.59-6.61 (1H), 6.82-6.90 (3H), 7.01-7.06 (1H)

Example 147 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylcyclohexylcarbamate

¹H-NMR (d₆-Acetone): 1.02-1.20 (3H), 1.20-1.30 (2H), 1.51-1.54 (3H),1.54-1.57 (1H), 1.61-1.68 (2H), 1.75-1.82 (2H), 2.22-2.24 (3H),2.30-2.33 (3H), 3.22-3.30 (1H), 4.60-4.64 (1H), 5.31-5.34 (1H),5.54-5.57 (1H), 6.60-6.62 (1H), 6.82-6.83 (1H), 6.83-6.87 (1H),6.95-6.98 (1H), 7.03-7.04 (1H)

Example 148{2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl[2-(2,4-dichlorophenyl)ethyl]carbamate

¹H-NMR (d₆-Acetone): 1.50-1.56 (3H), 2.22-2.24 (3H), 2.30-2.32 (3H),2.85-2.90 (2H), 3.30-3.35 (2H), 4.60-4.64 (1H), 5.30-5.33 (1H),5.55-5.58 (1H), 6.60-6.62 (1H), 6.82-6.90 (2H), 6.96-6.98 (1H),7.03-7.04 (2H), 7.19-7.24 (2H), 7.40-7.41 (1H)

Example 149 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylcyclohexyl(methyl)carbamate

¹H-NMR (d₆-Acetone): 1.00-1.10 (1H), 1.20-1.40 (4H), 1.41-1.60 (6H),1.70-1.80 (2H), 2.10-2.16 (3H), 2.30-2.42 (6H), 4.61-4.70 (1H),5.40-5.60 (2H), 6.62-6.65 (1H), 6.81-6.82 (1H), 6.83-6.98 (2H),7.10-7.15 (1H)

Example 150 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylbenzyl(methyl)carbamate

¹H-NMR (d₆-Acetone): 1.41-1.59 (3H), 2.18-2.26 (3H), 2.30-2.40 (3H),2.70-2.80 (3H), 4.00-4.05 (1H), 4.25-4.38 (1H), 4.60-4.73 (1H),5.59-5.69 (2H), 6.60-6.70 (1H), 6.80-7.00 (3H), 7.01-7.06 (1H),7.10-7.19 (2H), 7.20-7.33 (3H)

Example 151 {2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylmethyl(2-phenylethyl)carbamate

¹H-NMR (d₆-Acetone): 1.33-1.41 (3H), 1.50-1.56 (3H), 2.17-2.20 (1H),2.20-2.22 (3H), 2.22-2.26 (2H), 2.36-2.39 (3H), 2.45-2.55 (1H),4.62-4.70 (1H), 5.60-5.70 (2H), 6.67-6.70 (1H), 6.82-6.92 (3H),7.10-7.18 (2H), 7.18-7.24 (2H), 7.24-7.27 (2H)

Example 1521-(1-{2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}ethyl) 2-methyl(2S)-pyrrolidine-1,2-dicarboxylate

¹H-NMR (CD₃OD): 1.10-1.13 (3H), 1.56-1.60 (3H), 1.85-1.90 (3H),2.20-2.24 (1H), 2.30-2.32 (3H), 2.39-2.41 (3H), 3.40-3.50 (2H),3.60-3.63 (1H), 3.70-3.75 (2H), 4.29-4.33 (1H), 4.79-4.83 (1H),6.10-6.13 (1H), 6.37-6.40 (1H), 6.90-9.93 (1H), 7.00-7.03 (1H),7.20-7.23 (1H)

Example 153 2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-methyl-1H-imidazole

To a mixture of the compound of Example 58 (100 mg, 0.5 mmol) andcaesium carbonate (407 mg, 1.25 mmol) in acetone (4 ml) was addediodomethane (78 μl, 1.25 mmol). The reaction mixture was stirred at roomtemperature, under nitrogen, for 4 h and then concentrated in vacuo. tothe residue was added water (10 ml) and the solution was extracted withethyl acetate (2×10 ml). The combined extracts were dried (MgSO₄) andconcentrated in vacuo.

The residue was dissolved in methanol (1 ml) and purified by automatedpreparative liquid chromatography (Gilson system, 150 mm×21.4 mm LUNAC18(2) 5 μm column, 20 ml/min) using an acetonitrile:water gradient[20:80 (3 min) to 98:2 (16 min)]. The appropriate fractions werecombined and concentrated to give the title compound (40 mg).

Experimental MH⁺ 215.3; expected 215.1 ¹H-NMR (d₆-Acetone): 1.45-1.50(3H), 2.20-2.30 (6H), 3.10-3.15 (3H), 4.35-4.45 (1H), 6.55-6.60 (1H),6.80-6.85 (1H), 6.85-6.90 (2H), 6.90-6.95 (1H) Rhip. Funct. ED₁₀₀mg/cm²=0.3

Similarly prepared from Example 1 was:

MH⁺ Rhip. Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor Expected mg/cm² 154

(Bromomethyl) cyclopropane 255.2; 255.2 1

Example 1541-(Cyclopropylmethyl)-2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 0.00-0.05 (1H), 0.10-0.20 (1H), 0.30-0.45 (2H),0.80-0.90 (1H), 1.50-1.60 (3H), 2.20-2.30 (6H), 3.30-3.50 (2H),4.40-4.50 (1H), 6.60-6.65 (1H), 6.80-6.90 (2H), 6.90-6.95 (1H),7.05-7.10 (1H)

Similarly prepared from Example 58 was:

MH⁺ Rhip. Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor Expected mg/cm² 155

Bromoethane 229.2; 229.2 1

Example 155 2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-ethyl-1H-imidazole

¹H-NMR (d₆-Acetone): 0.90-1.00 (3H), 1.50-1.60 (3H), 2.20-2.35 (6H),3.50-3.70 (2H), 4.40-4.50 (1H), 6.60-6.63 (1H), 6.80-6.90 (2H),6.90-7.00 (2H)

Example 156 {2-[1-(2,5-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpivalate

To a mixture of the compound of Example 17 (58 mg, 0.29 mmol) andcaesium carbonate (236 mg, 0.72 mmol) in acetone (5 ml) was addedchloromethyl pivalate (87 mg, 0.58 mmol). The reaction mixture wasstirred at room temperature and under nitrogen for 18 h and thenconcentrated in vacuo. To the residue was added diethyl ether and thesolution was passed through a silica plug (10 g), eluting with diethylether. The appropriate fractions were combined and concentrated to givethe title compound (78 mg).

¹H-NMR (CDCl₃): 1.01-1.05 (9H), 1.61-1.65 (3H), 2.13-2.16 (3H),2.35-2.37 (3H), 4.38-4.44 (1H), 5.34-5.38 (1H), 5.47-5.51 (1H),6.65-6.67 (1H), 6.85-6.89 (1H), 6.96-7.02 (3H)

Experimental MH⁺ 315.4; expected 315.2Rhip. Funct. ED₁₀₀ mg/cm²<=10

Similarly prepared by alkylation with chloromethyl pivalate were:

MH⁺ Rhip. Funct. Ex. From Found/ ED₁₀₀ No. Ar Ex. Expected mg/cm² 157

26 331.3 331.2 <=10 158

16 355.3 355.2 0.3, 1 159

24 355.3 355.2 <=10 160

20 301.2 301.2 0.1 161

18 315.2 315.2 >1 162

39 321.1 321.1 0.3 163

37 355.2 355.1 <=10 164

27 329.4 329.2 <=1, 1 165

43 355.1 355.1 >1 166

54 389.2 389.1 0.3 167

21 287.3 287.2 1, 0.3

Example 157{2-[1-(3-Methoxy-2-methylphenyl)ethyl]-1H-imidazol-1-yl}methyl pivalate

¹H-NMR (CDCl₃): 1.01-1.05 (9H), 1.61-1.65 (3H), 2.23-2.25 (3H),3.79-3.81 (3H), 4.45-4.55 (1H), 5.33-5.36 (1H), 5.42-5.46 (1H),6.40-6.43 (1H), 6.65-6.68 (1H), 6.96-7.01 (3H)

Example 158(2-{1-[2-(Trifluoromethyl)phenyl]ethyl}-1H-imidazol-1-yl)methyl pivalate

¹H-NMR (CDCl₃): 0.93-0.96 (9H), 1.69-1.73 (3H), 4.61-4.68 (1H),5.51-5.60 (2H), 6.98-7.01 (2H), 7.24-7.31 (2H), 7.37-7.42 (1H),7.61-7.64 (1H)

Example 159(2-{1-[3-(Trifluoromethyl)phenyl]ethyl}-1H-imidazol-1-yl)methyl pivalate

¹H-NMR (CDCl₃): 0.96-0.99 (9H), 1.68-1.72 (3H), 4.30-4.36 (1H),5.52-5.56 (1H), 5.65-5.69 (1H), 6.98-7.01 (2H), 7.36-7.38 (2H),7.42-7.45 (2H)

Example 160 {2-[1-(3-Methylphenyl)ethyl]-1H-imidazol-1-yl}methylpivalate

¹H-NMR (CDCl₃): 1.02-1.05 (9H), 1.68-1.71 (3H), 2.25-2.27 (3H),4.19-4.25 (1H), 5.51-5.62 (2H), 6.93-7.01 (4H), 7.11-7.16 (1H)

Example 161 {2-[1-(2,6-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpivalate

¹H-NMR (CDCl₃): 1.03-1.06 (9H), 1.72-1.76 (3H), 2.00-2.10 (6H),4.54-4.60 (1H), 5.13-5.17 (1H), 5.32-5.36 (1H), 6.92-7.02 (5H)

Example 162 {2-[1-(3-Chlorophenyl)ethyl]-1H-imidazol-1-yl}methylpivalate

¹H-NMR (CDCl₃): 1.00-1.03 (9H), 1.66-1.70 (3H), 4.20-4.27 (1H),5.51-5.66 (2H), 6.97-7.01 (2H), 7.04-7.08 (1H), 7.12-7.20 (3H)

Example 164 {2-[1-(2-Ethyl-3-methylphenyl)ethyl]-1H-imidazol-1-yl}methylpivalate

¹H-NMR (CD₃OD): 0.98-1.00 (9H), 1.20-1.24 (3H), 1.60-1.63 (3H),2.37-2.38 (3H), 2.80-2.86 (2H), 4.60-4.65 (1H), 5.53-5.56 (1H),5.66-5.70 (1H), 6.61-6.63 (1H), 6.90-6.95 (2H), 6.99-7.01 (1H),7.18-7.19 (1H)

Example 166(2-{1-[2-Chloro-3-(trifluoromethyl)phenyl]ethyl}-1H-imidazol-1-yl)methylpivalate

¹H-NMR (CDCl₃): 0.96-0.99 (9H), 1.69-1.72 (3H), 4.94-5.01 (1H),5.60-5.64 (1H), 5.72-5.76 (1H), 7.03-7.05 (2H), 7.26-7.30 (1H),7.40-7.43 (1H), 7.55-7.59 (1H)

Example 167 [2-(1-Phenylethyl)-1H-imidazol-1-yl]methyl pivalate

¹H-NMR (CDCl₃): 1.01-1.04 (9H), 1.68-1.72 (3H), 4.22-4.28 (1H),5.51-5.61 (2H), 6.96-7.00 (2H), 7.13-7.19 (3H), 7.22-7.27 (2H)

Example 168 3-[1-(1H-Imidazol-2-yl)ethyl]benzonitrile

To a solution of the compound of Preparation 196 (264 mg, 1.23 mmol) inanhydrous N,N-dimethyl formamide (3 ml), at −15° C., was added dropwisethionyl chloride (0.20 ml, 2.7 mmol). The reaction mixture was allowedto warm to 0° C. over 4 h and then poured into an ice:water mixture. Themixture was extracted with ethyl acetate and the extracts were dried(MgSO₄) and concentrated in vacuo. The residue was dissolved in warmmethanol (1 ml) and purified by automated preparative liquidchromatography (Gilson system, 150 mm×50 mm Sunfire C18 10 μm column,120 ml/min) using an acetonitrile:water gradient [20:80 (2 min) to 95:5(18.5 min)]. The appropriate fractions were combined and concentrated togive the title compound (7 mg).

Experimental MH⁺ 198.1; expected 198.1 ¹H-NMR (CDCl₃): 1.68-1.72 (3H),4.22-4.26 (1H), 6.97-7.00 (2H), 7.40-7.43 (1H), 7.50-7.55 (3H) Rhip.Funct. ED₁₀₀ mg/cm²=>1

Example 169 1-Benzyl-2-[1-(3-methyl phenyl)ethyl]-1H-imidazole

To a mixture of the compound of Example 20 (500 mg, 2.68 mmol) andcaesium carbonate (2.19 g, 6.71 mmol) in acetone (20 ml) was addedbenzyl bromide (0.64 ml, 5.37 mmol). The reaction mixture was stirred atroom temperature for 18 h, filtered through Celite® and thenconcentrated in vacuo. The residue was dissolved in acetonitrile (2 ml)and purified by automated preparative liquid chromatography (Gilsonsystem, 150 mm×50 mm LUNA C18(2) 10 μm column, 40 ml/min) using anacetonitrile:water gradient [50:50 (20 min) to 95:5 (21 min)]. Theappropriate fractions were combined and concentrated to give the titlecompound (272 mg).

Experimental MH⁺ 277.4; expected 277.2 ¹H-NMR (d₆-Acetone): 1.57-1.60(3H), 2.11-2.12 (3H), 4.08-4.13 (1H), 4.90-4.95 (1H), 5.01-5.06 (1H),6.90-6.91 (1H), 6.91-7.00 (6H), 7.10-7.14 (1H), 7.21-7.25 (3H) Rhip.Funct. ED₁₀₀ mg/cm²=>1

Example 170 1-Methyl-2-[1-(3-methylphenyl)ethyl]-1H-imidazole

To a mixture of the compound of Example 20 (500 mg, 2.68 mmol) andcaesium carbonate (2.19 g, 6.71 mmol) in acetone (20 ml) was addedmethyl iodide (0.33 ml, 5.37 mmol). The reaction mixture was stirred atroom temperature for 2 h, filtered through Celite® and then concentratedin vacuo. The residue was dissolved in acetonitrile (2 ml) and purifiedby automated preparative liquid chromatography (Gilson system, 150 mm×50mm LUNA C18(2) 10 μm column, 40 ml/min) using an acetonitrile:watergradient [50:50 (20 min) to 95:5 (21 min)]. The appropriate fractionswere combined and concentrated to give the title compound (230 mg).

Experimental MH⁺ 201.4; expected 201.1 ¹H-NMR (d₆-Acetone): 1.59-1.62(3H), 2.12-2.14 (3H), 4.17-4.21 (1H), 6.80-6.81 (1H), 6.89-6.90 (1H),6.96-7.02 (3H), 7.14-7.17 (1H) Rhip. Funct. ED₁₀₀ mg/cm²=>1

Example 171 1-{2-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}ethylmorpholine-4-carboxylate

To a mixture of the compound of Example 1 (100 mg, 0.5 mmol) and caesiumcarbonate (163 mg, 0.5 mmol) in anhydrous acetone (2 ml) was addedPreparation 134 (96 mg, 0.50 mmol) in anhydrous acetone (1 ml). Thereaction mixture was stirred at room temperature for 14 days and thendiluted with water (5 ml) and ethyl acetate (5 ml). The two layers wereseparated and the aqueous phase was extracted with ethyl acetate (2×5ml). The combined organic phases were dried (MgSO₄) and concentrated invacuo. The residue was dissolved in acetonitrile (1.5 ml) and purifiedby automated preparative liquid chromatography (Gilson system, 150mm×21.4 mm LUNA C18(2) 5 μm column, 20 ml/min) using anacetonitrile:water gradient [20:80 (3 min) to 98:2 (16 min)]. Theappropriate fractions were combined and concentrated to give the titlecompound (6 mg).

Retention time 6.13 min (Gilson system, 150 mm×4.6 mm LUNA C18(2) 5 μmcolumn, 15 ml/min) using a 0.1% trifluoroacetic acid:acetonitrilegradient [95:5 (5 min) to 2:98 (9 min)].

Experimental MH⁺ 358.5; expected 358.2 ¹H-NMR (CD₃OD): 1.55-1.60 (3H),1.62-1.65 (3H), 2.27-2.30 (3H), 2.30-2.33 (3H), 2.90-3.00 (2H),3.39-3.49 (2H), 4.61-4.65 (1H), 6.50-6.56 (2H), 6.85-6.89 (1H),6.99-7.03 (1H), 7.17-7.18 (1H) Rhip. Funct. ED₁₀₀ mg/cm²=1

Example 172{2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl pivalate

To a mixture of the compound of Example 58 (500 mg, 2.5 mmol) andcaesium carbonate (1.79 g, 5.5 mmol) in anhydrous acetone (10 ml) wasadded chloromethyl pivalate (0.43 ml, 3.0 mmol). The reaction mixturewas stirred at room temperature for 18 h. To the mixture was addeddichloromethane (10 ml) and water (10 ml) and the two layers wereseparated. The aqueous phase was extracted with dichloromethane (2×10ml) and the combined organic phases were dried (MgSO₄) and concentratedin vacuo.

The residue was dissolved in acetonitrile (2 ml) and purified byautomated preparative liquid chromatography (Gilson system, 250 mm×50 mmLUNA C18(2) 10 μm column, 120 ml/min) using an acetonitrile:watergradient [55:45 (20 min) to 95:5 (20.5 min)]. The appropriate fractionswere combined and concentrated to give the title compound (410 mg).

Experimental MH⁺ 315.2; expected 315.2 ¹H-NMR (d₆-Acetone): 0.97-1.00(9H), 1.57-1.60 (3H), 2.28-2.30 (3H), 2.37-2.39 (3H), 4.60-4.65 (1H),5.56-5.60 (1H), 5.65-5.69 (1H), 6.75-6.78 (1H), 6.90-7.00 (3H),7.12-7.13 (1H)

Example 1732-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-(3,3,3-trifluoropropyl)-1H-imidazole

To a mixture of the preparation of Example 58 (50 mg, 0.25 mmol) andcaesium carbonate (203 mg, 0.62 mmol) in acetonitrile (2.5 ml) was added1,1,1-trifluoro-3-iodopropane (73 μl, 0.62 mmol). The reaction mixturewas heated at 100° C. in a microwave (200 W) for 45 min and thenconcentrated in vacuo. To the residue was added water (10 ml) and themixture was extracted with ethyl acetate (2×10 ml). The combinedextracts were dried (MgSO₄) and concentrated in vacuo.

The residue was dissolved in acetonitrile (1 ml) and diethylamine (2-3drops) and purified by automated preparative liquid chromatography(Gilson system, 150 mm×30 mm LUNA C18(2) 10 μm column, 40 ml/min) usingan acetonitrile:water gradient [50:50 (20 min) to 98:2 (20.1 min)]. Theappropriate fractions were combined and concentrated to give the titlecompound (20 mg).

Experimental MH⁺ 297.3; expected 297.2 ¹H-NMR (d₆-Acetone): 1.55-1.60(3H), 1.79-1.90 (1H), 2.23-2.25 (3H), 2.43-2.62 (4H), 3.81-3.89 (2H),4.46-4.53 (1H), 6.58-6.61 (1H), 6.85-6.92 (2H), 6.96-6.99 (1H),7.06-7.08 (1H) Rhip. Funct. ED₁₀₀ mg/cm²<=10

Similarly prepared from Example 58 was:

MH⁺ Rhip. Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor Expected mg/cm² 174

2-Bromopropane 243.3 243.2 >1

Example 1742-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1-isopropyl-1H-imidazole

¹H-NMR (d₆-Acetone): 0.80-0.83 (3H), 1.29-1.32 (3H), 1.57-1.59 (3H),2.25-2.27 (3H), 2.30-2.32 (3H), 4.00-4.06 (1H), 4.41-4.45 (1H),6.58-6.60 (1H), 6.85-6.88 (2H), 6.95-6.97 (1H), 7.06-7.07 (1H)

Example 1752-[1-(2,3-Dimethylphenyl)ethyl]-1-(4-methoxybenzyl)-1H-imidazole

To a solution of the compound of Example 1 (100 mg, 0.5 mmol) andN,N-diisopropylethylamine (77 mg, 0.6 mmol) in dichloromethane, undernitrogen, was added 4-methoxybenzyl bromide (151 mg, 0.75 mmol). Thereaction mixture was stirred at room temperature for 90 min and water(10 ml) was added. The layers were separated, and the aqueous layerwashed with dichloromethane (15 ml). The combined organics were dried(MgSO₄) and concentrated in vacuo.

The residue was dissolved in methanol:water (9:1, 3 ml) and purified byautomated preparative liquid chromatography (Gilson system, 150 mm×4.6mm LUNA C18(2) 10 μm column, 20 ml/min) using an acetonitrile:watergradient [60:40 to 95:5]. The appropriate fractions were concentrated invacuo to give the title compound (10 mg).

Experimental MH⁺ 321.5; expected 321.2 ¹H-NMR (d₆-Acetone): 1.48-1.53(3H), 2.16-2.21 (3H), 2.21-2.24 (3H), 3.70-3.75 (3H), 4.31-4.36 (1H),4.58-4.64 (1H), 4.74-4.81 (1H), 6.62-6.69 (1H), 6.72-6.82 (4H),6.85-6.98 (4H) Rhip. Funct. ED₁₀₀ mg/cm²=0.3

Similarly prepared from Example 1 were:

MH⁺ Rhip. Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor Expected mg/cm² 176

1-(Bromomethyl)-4- (trifluoromethyl)benzene 359.3 359.2 >1, 1 177

Bromo(methoxy)methane 245.4 245.2 0.1

Example 1762-[1-(2,3-Dimethylphenyl)ethyl]-1-[4-(trifluoromethyl)benzyl]-1H-imidazole

¹H-NMR (d₆-Acetone): 1.51-1.58 (3H), 2.12-2.21 (6H), 4.32-4.40 (1H),4.91-4.99 (1H), 5.08-5.16 (1H), 6.68-6.78 (1H), 6.84-6.92 (2H),6.96-7.06 (3H), 7.07-7.12 (1H), 7.48-7.56 (2H)

Example 177 2-[1-(2,3-Dimethylphenyl)ethyl]-1-(methoxymethyl)-1H-imidazole

¹H-NMR (d₆-Acetone): 1.54-1.60 (3H), 2.28-2.32 (3H), 2.33-2.37 (3H),3.04-3.09 (3H), 4.54-4.61 (1H), 4.82-4.90 (1H), 4.92-4.99 (1H),6.72-6.78 (1H), 6.88-7.00 (3H), 7.08-7.12 (1H)

Example 1782-[1-(2,3-Dimethylphenyl)ethyl]-1-(2-methoxybenzyl)-1H-imidazole

1-(Bromomethyl)-2-methoxybenzene (J. Indian Chem. Soc.; 28, 1951, 277;150 mg, 0.75 mmol) was added to a suspension of the compound of Example1 (100 mg, 0.5 mmol) and caesium carbonate (406 mg, 1.2 mmol) in acetone(4 ml), under a nitrogen atmosphere. The reaction mixture was stirred atroom temperature for 18 h. The mixture was filtered and the filtrate wasconcentrated in vacuo. To the residue was added water (10 ml) and ethylacetate (10 ml) and the two layers were separated. The aqueous layer waswashed with a further portion of ethyl acetate (10 ml) and the combinedorganic layers were dried (MgSO₄) and concentrated in vacuo.

The residue was dissolved in methanol:water (9:1, 2 ml) and purified byautomated preparative liquid chromatography (Gilson system, 150 mm×30 mmLUNA C18(2) 10 μm column, 40 ml/min) using an acetonitrile:watergradient [20:80 to 98:2]. The appropriate fractions were concentrated invacuo to give the title compound (24 mg).

Experimental MH⁺ 321.5; expected 321.2 ¹H-NMR (d₆-Acetone): 1.48-1.53(3H), 2.14-2.19 (3H), 2.20-2.26 (3H), 3.78-3.82 (3H), 4.32-4.40 (1H),4.64-4.78 (2H), 6.49-6.54 (1H), 6.68-6.72 (1H), 6.73-6.80 (1H),6.86-6.98 (5H), 7.19-7.24 (1H) Rhip. Funct. ED₁₀₀ mg/cm²<=10

Example 179 1-Benzyl-2-[1-(2-fluoro-3-methylphenyl)ethyl]-1H-imidazole

To a solution of the compound of Example 7 (69 mg, 0.34 mmol) andtriethylamine (57 μl, 0.41 mmol) in anhydrous tetrahydrofuran (3 ml),under nitrogen, was added benzyl bromide (81 μl, 0.68 mmol). Thereaction mixture was stirred at room temperature for 11 days and thenconcentrated in vacuo. To the residue was added saturated aqueous sodiumhydrogen carbonate solution (10 ml) and the mixture was extracted withethyl acetate (2×10 ml). The combined extracts were dried (MgSO₄),filtered through silica and the filtrate was concentrated in vacuo togive the title compound (66 mg).

Experimental MH⁺ 295.2; expected 295.2 ¹H-NMR (d₆-Acetone): 1.56-1.60(3H), 2.19-2.22 (3H), 4.43-4.50 (1H), 4.95-5.00 (1H), 5.04-5.10 (1H),6.90-6.99 (5H), 7.00-7.04 (2H), 7.10-7.17 (3H)

Rhip. Funct. ED₁₀₀ mg/cm²=1

Example 180 4-Fluorophenyl2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

To a solution of the compound of Example 1 (100 mg, 0.5 mmol) inanhydrous tetrahydrofuran (2 ml) was added triethylamine (0.08 ml, 0.6mmol), followed by 4-fluorophenyl chloroformate (0.26 ml, 2.0 mmol). Thereaction mixture was then stirred at room temperature, under nitrogen,for 1 h. To the mixture was added ethyl acetate (10 ml) and water (10ml) and the two layers were separated. The aqueous layer was washed withethyl acetate (10 ml) and the combined organic phases were dried (MgSO₄)and concentrated in vacuo.

The residue was dissolved in acetonitrile (1 ml) and purified byautomated preparative liquid chromatography (Gilson system, 150 mm×30 mmLUNA C18(2) 10 μm column, 40 ml/min) using an acetonitrile:watergradient [55:45 (20 min) to 98:2 (20.1 min)]. The appropriate fractionswere concentrated in vacuo to give the title compound (60 mg).

Experimental MH⁺ 339.3; expected 339.1 ¹H-NMR (d₆-Acetone): 1.50-1.60(3H), 2.15-2.25 (6H), 4.40-4.50 (1H), 6.80-6.85 (1H), 6.90-7.00 (3H),7.00-7.05 (1H), 7.15-7.25 (2H), 7.35-7.40 (1H) Rhip. Funct. ED₁₀₀mg/cm²=0.03

Example 181 Benzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

To a solution of the compound of Example 58 (7.50 g, 37.4 mmol) andtriethylamine (5.74 ml, 41.2 mmol) in dichloromethane (100 ml), cooledin an ice bath, was added dropwise benzyl chloroformate (21.4 ml, 150mmol). The reaction mixture was allowed to warm to room temperature andstirred under nitrogen for 3 h. The mixture was cooled, before additionof aqueous sodium hydrogen carbonate solution and dichloromethane andthe two layers were separated. The aqueous phase was extracted withdichloromethane and the combined organic phases were dried (MgSO₄) andconcentrated in vacuo. To the residue was added cyclohexane and thesolution was filtered and concentrated in vacuo.

The residue was purified by flash chromatography (silica) with gradientelution, ethyl acetate cyclohexane [10:90 to 100:0]. The appropriatefractions were combined and concentrated to give the title compound(9.96 g).

Experimental MH⁺ 335.2; expected 335.2 ¹H-NMR (d₆-Acetone): 1.50-1.53(3H), 2.22-2.29 (6H), 5.05-5.10 (1H), 5.23-5.25 (2H), 6.50-6.52 (1H),6.83-6.87 (1H), 6.97-7.00 (2H), 7.28-7.31 (2H), 7.35-7.38 (3H),7.50-7.51 (1H) Rhip. Funct. ED₁₀₀ mg/cm²=>0.03

Similarly prepared from Example 1 was:

Rhip. MH⁺ Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor Expected mg/cm² 182

Isopropyl chlorocarbonate 287.4 287.2 0.03

Example 182 Isopropyl2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.10-1.20 (6H), 1.45-1.55 (3H), 2.20-2.35 (6H),4.90-5.00 (1H), 5.00-5.10 (1H), 6.40-6.45 (1H), 6.80-6.85 (1H),6.90-7.00 (2H), 7.40-7.45 (1H)

Example 183 Isobutyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

To a solution of the compound of Example 58 (1.00 g, 5.0 mmol) andtriethylamine (0.77 ml, 5.5 mmol) in anhydrous dichloromethane (10 ml)was added drop wise isobutyl chloroformate (2.60 ml, 20 mmol). Thereaction mixture was stirred at room temperature for 18 h and thenconcentrated in vacuo. The residue was partitioned between water (10 ml)and ethyl acetate (10 ml) and the two layers were separated. The aqueouslayer was extracted with ethyl acetate (10 ml) and the combined organiclayers were dried (MgSO₄) and concentrated in vacuo.

The residue was dissolved in acetonitrile:water (9:1, 4 ml) and purifiedby automated preparative liquid chromatography (Gilson system, 150 mm×30mm LUNA C18(2) 5 μm column, 40 ml/min) using an acetonitrile:watergradient [65:35 to 95:5]. The appropriate fractions were combined andconcentrated to give the title compound (150 mg).

Experimental MH⁺ 301.4; expected 301.2 ¹H-NMR (CDCl₃): 0.89-0.95 (6H),1.60-1.63 (3H), 1.91-2.00 (1H), 2.28-2.39 (6H), 3.95-4.04 (2H),5.05-5.11 (1H), 6.62-6.65 1H), 6.90-7.01 (3H), 7.40-7.41 (1H) Rhip.Funct. ED₁₀₀ mg/cm²=0.03

Similarly prepared by acylation with isobutyl chlorocarbonate were:

MH⁺ Rhip. Funct. Ex. From Found/ ED₁₀₀ No. Ar Ex. Expected mg/cm² 184

52 305.4 305.2 0.3 185

29 323.6 323.2 1 186

1 301.4 301.2 0.01

Example 184 Isobutyl 2-[1-(3-fluoro-2-methylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (CDCl₃): 0.83-0.95 (6H), 1.60-1.64 (3H), 1.91-1.99 (1H),2.35-2.38 (3H), 3.97-4.02 (2H), 5.00-5.03 (1H), 6.59-6.61 (1H),6.80-6.85 (1H), 6.98-7.03 (2H), 7.39-7.40 (1H)

Example 185 Isobutyl 2-[1-(2,6-difluoro-3-methylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (CDCl₃): 0.85-0.96 (6H), 1.74-1.78 (3H), 1.95-2.00 (1H),2.17-2.20 (3H), 3.98-4.04 (2H), 4.99-5.03 (1H), 6.65-6.71 (1H),6.90-6.97 (2H), 7.39-7.41 (1H)

Example 186 Isobutyl2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.80-0.90 (6H), 1.40-1.50 (3H), 1.80-1.90 (1H),2.20-2.30 (6H), 3.90-4.00 (2H), 5.00-5.10 (1H), 6.45-6.50 (1H),6.80-6.85 (1H), 6.90-6.95 (2H), 7.45-7.50 (1H)

Example 1872-[1-(2,3-Dimethylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide

To a solution of the compound of Example 1 (100 mg, 0.5 mmol) andtriethylamine (77 μl, 0.55 mmol) in anhydrous tetrahydrofuran (4 ml),was added dimethylsulphamoyl chloride (59 μl, 0.55 mmol). The reactionmixture was stirred at 60° C., under nitrogen, for 36 h and thenconcentrated in vacuo. The residue was partitioned between water (10 ml)and ethyl acetate (10 ml) and the two layers were separated. The aqueouslayer was extracted with ethyl acetate (10 ml) and the combined organiclayers were dried (MgSO₄) and concentrated in vacuo.

The residue was dissolved in methanol (1.5 ml) and purified by automatedpreparative liquid chromatography (Gilson system, 150 mm×50 mm LUNAC18(2) 10 μm column, 120 ml/min) using an acetonitrile:water gradient[20:80 to 95:5]. The appropriate fractions were combined andconcentrated to give the title compound (49 mg).

Experimental MH⁺ 308.2; expected 308.1 ¹H-NMR (d₆-Acetone): 1.50-1.56(3H), 2.22-2.26 (3H), 2.31-2.36 (3H), 2.50-2.57 (6H), 4.95-5.01 (1H),6.70-6.74 (1H), 6.85-6.95 (2H), 7.00-7.04 (1H), 7.40-7.41 (1H) Rhip.Funct. ED₁₀₀ mg/cm²<=10

Example 188 2-Ethoxy-1-(ethoxymethyl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

To a mixture of Example 58 (500 mg, 2.5 mmol) and pyridine (0.44 ml, 5.5mmol) in anhydrous dichloromethane (5 ml), at 0° C. and under nitrogen,was added phosgene (20% in toluene, 1.44 ml, 2.75 mmol). The mixture wasstirred at 0° C. for 20 min, before addition of 1,3-diethoxypropan-2-ol(407 mg, 2.75 mmol). The reaction mixture was stirred at roomtemperature for 30 min and then poured into ice water (10 ml). Themixture was adjusted to pH 7 by addition of solid sodium hydrogencarbonate and the two layers were separated. The aqueous phase wasextracted with dichloromethane (2×10 ml) and the combined extracts weredried (MgSO₄) and concentrated in vacuo.

The residue was dissolved in methanol (1.5 ml) and purified by automatedpreparative liquid chromatography (Gilson system, 150 mm×50 mm SunfireC18 10 μm column, 120 ml/min) using an acetonitrile:water gradient[60:40 (20 min) to 98:2 (20.5 min)]. The appropriate fractions werecombined and concentrated to give the title compound (435 mg).

Experimental MH⁺ 375.2; expected 375.2 ¹H-NMR (d₆-Acetone): 0.97-1.02(3H), 1.05-1.10 (3H), 1.55-1.59 (3H), 2.25-2.28 (3H), 2.32-2.35 (3H),3.32-3.50 (5H), 3.52-3.58 (3H), 5.05-5.12 (1H), 6.54-6.57 (1H),6.84-6.89 (1H), 6.96-6.99 (2H), 7.49-7.50 (1H) Rhip. Funct. ED₁₀₀mg/cm²=0.03

Example 189 Cyclopropylmethyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

To a mixture of the compound of Example 58 (100 mg, 0.5 mmol) andpyridine (90 μl, 1.1 mmol) in anhydrous acetonitrile (1 ml), at 0° C.and under nitrogen, was added diphosgene (33 μl, 0.28 mmol). The mixturewas stirred at 0° C. for 30 min, before addition of cyclopropylmethanol(43 μl, 0.55 mmol). The reaction mixture was stirred at room temperaturefor 1 h and then filtered. The filtrate was purified by automatedpreparative liquid chromatography (Gilson system, 150 mm×22.4 mm LUNAC18(2) 5 μm column, 20 ml/min) using an acetonitrile:water gradient[15:85 (3 min) to 98:2 (16 min)]. The appropriate fractions werecombined and concentrated to give the title compound (30 mg).

Experimental MH⁺ 299.4; expected 299.2 ¹H-NMR (CDCl₃): 0.20-0.30 (2H),0.50-0.60 (2H), 1.02-1.10 (1H), 1.59-1.65 (3H), 2.30-2.29 (6H),3.96-4.05 (2H), 5.03-5.10 (1H), 6.62-6.65 (1H), 6.91-7.00 (3H),7.40-7.41 (1H) Rhip. Funct. ED₁₀₀ mg/cm²=0.03

Similarly prepared from Example 58 were:

Rhip. MH⁺ Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor Expected mg/cm² 190

2-Isopropoxyethanol 331.8 331.2 <=10 191

3-(3-Propoxypropoxy)- propan-1-ol 403.5 403.3 <=10 192

2-Ethoxyethanol 317.2 317.2 0.03 193

Cyclobutanol 300.0 299.2 <=10 194

2-Cyclohexylethanol 355.2 355.2 0.03 195

Tetrahydro-2H-pyran- 4-ylmethanol 343.9 343.2 <=10 196

3-(3-Methoxypropoxy)- propan-1-ol 375.2 375.2 0.03 197

(2-Methylcyclopropyl)- methanol 270.0 269.2 decar- boxylates <=10 198

3-[3-(3-Butoxy- propoxy)-propoxy]- propan-1-ol 476.1 475.3 >0.03 199

2,2,2-Trifluoroethanol 327.9 327.1 <=10 200

Cyclobutylmethanol 313.2 313.2 0.03 201

(1-Methylcyclopropyl)- methanol 313.9 313.2 202

2-Cyclopropylethanol 313.8 313.2 <=10 203

1,3-Dimethoxypropan- 2-ol 348.0 347.2 >0.03 204

(3-Methyloxetan-3- yl)methanol 329.9 329.2 >0.03 205

5-Methylhexan-1-ol 300.0 299.2 de- carboxyl >0.03 206

3-(4-Fluorophenoxy)- propan-1-ol 397.2 397.2 0.03 207

2,2,3,3,3-Pentafluoro- propan-1-ol 377.8 377.1 <=10 208

2-(Methylthio)ethanol 319.8 319.1 <=10 209

Ethanol 273.7 273.2 >0.03 210

3-Cyclohexylpropan-1- ol 369.9 369.3 <=10 211

3-Methylbutan-1-ol 315.7 315.2 >0.03 212

2-Isopropylcyclo- hexanol 369.9 369.3 ≦10 213

2-Methoxyethanol 303.2 303.2 <=0.03, 0.1 214

Tetrahydro-2H-pyran- 4-ol 370.8 (MeCN adduct) 370.2 <=0.03 215

3-Cyclopentylpropan- 1-ol 355.9 355.2 >0.03 216

1-Methylpiperidin-4-ol 342.9 342.2 <=10 217

4,4,4-Trifluorobutan-1-ol 355.2 355.2 0.03 218

Cyclopentanol 313.8 313.2 <=10 219

(1-Methylcyclohexyl)- methanol — >0.03 220

Cyclopentylmethanol 328.1 327.2 <=10 221

4-Methylpentan-1-ol 329.8 329.2 >0.03 222

(1-Propylcyclobutyl)- methanol 355.9 355.2 >0.03 223

2-[(4-Chlorophenyl)- thio]ethanol 415.9 415.1 >0.03 224

(2S)-2-Methylbutan-1-ol 316.0 315.2 >0.03 225

3-(Methylthio)propan-ol 333.8 333.2 >0.03 226

Cyclohexylmethanol 341.2 341.2 0.03 227

3-Ethoxypropan-1-ol 332.0 331.2 >0.03 228

2-Methylcyclohexanol — >0.03 229

2-(2,6-Dimethyl- morpholin-4-yl)ethanol 387.1 386.2 <=10 230

Pentan-1-ol 315.8 315.2 <=10 231

trans-4-Methyl- cyclohexanol 298.1 297.2 decar- boxylates <=10 232

2-Propylpentan-1-ol — >0.03 233

2-Ethylbutan-1-ol — <=10 234

2,2-Dimethylpropan-1-ol 315.8 315.2 <=10 235

Bicyclo[2.2.1]hept-2-yl- methanol 354.0 353.2 >0.03 236

3,3-Dimethylbutan-1-ol 330.1 329.2 >0.03 237

4-Isopropylcyclo- hexanol 369.3 369.3 <=0.03 <=0.01 238

3-(Ethylthio)propan-1-ol 347.9 347.2 >0.03 239

Propan-1-ol 287.7 287.2 >0.03 240

3-Methoxy-3- methylbutan-1-ol 346.0 345.2 >0.03 241

3-(Dimethylamino)-2,2- dimethylpropan-1-ol 359.0 358.2 <=10 242

4-Methoxybutan-1-ol 332.1 331.2 >0.03 243

2,2,4-Trimethylpentan-1-ol 357.3 357.3 0.03 244

Butan-1-ol 301.8 301.2 >0.03 245

3-Fluoro-3-methyl- butan-1-ol 333.8 333.2 >0.03 246

2-Isobutoxyethanol 346.0 345.2 0.1 247

4-Cyclohexylbutan-1-ol 383.3 383.3 0.1 248

4-Methylpent-3-en-1-ol 327.9 327.2 <=10 249

Pentan-3-ol 315.9 315.2 >0.03 250

(2S)-Pentan-2-ol — >0.03 251

(3S)-3,7-Dimethyl- octan-1-ol 386.1 385.3 >0.03 252

2-Propoxyethanol 331.8 331.2 >0.03 253

2,3-Dimethylpentan-1-ol 343.2 343.2 0.1 254

2,2-Dimethylbutan-1-ol — >0.03 255

Methyl 3-hydroxy-2,2- dimethylpropanoate 360.0 359.2 <=10

Example 190 2-Isopropoxyethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.00-1.09 (6H), 1.51-1.55 (3H), 2.25-2.27 (3H),2.36-2.38 (3H), 3.50-3.63 (3H), 4.32-4.36 (2H), 5.08-5.12 (1H),6.55-6.58 (1H), 6.82-6.87 (1H), 6.95-6.98 (2H), 7.45-7.47 (1H)

Example 191 3-(3-Propoxypropoxy)propyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.81-0.92 (3H), 0.97-1.13 (6H), 1.42-1.53 (2H),1.57-1.60 (3H), 2.25-2.40 (6H), 3.21-3.40 (4H), 3.50-3.61 (3H),5.00-5.15 (2H), 6.50-6.58 (1H), 6.83-6.91 (1H), 6.95-6.98 (2H),7.47-7.50 (1H)

Example 192 2-Ethoxyethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.02-1.09 (3H), 1.52-1.57 (3H), 2.24-2.26 (3H),2.37-2.39 (3H), 3.40-3.48 (2H), 3.59-3.66 (2H), 4.30-4.37 (2H),5.05-5.11 (1H), 6.55-6.58 (1H), 6.84-6.90 (1H), 6.95-6.99 (2H),7.48-7.49 (1H)

Example 193 Cyclobutyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.53-1.56 (3H), 1.60-1.65 (1H), 1.70-1.75 (1H),1.98-2.08 (2H), 2.22-2.30 (5H), 2.36-2.39 (3H), 4.98-5.06 (2H),6.48-6.50 (1H), 6.84-6.87 (1H), 6.95-6.98 (2H), 7.50-7.52 (1H)

Example 194 2-Cyclohexylethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.81-0.97 (2H), 1.10-1.30 (4H), 1.42-1.55 (5H),1.59-1.70 (5H), 2.27-2.29 (3H), 2.36-2.38 (3H), 4.20-4.30 (2H),5.04-5.09 (1H), 6.50-6.53 (1H), 6.85-6.89 (1H), 6.95-6.99 (2H),7.46-7.47 (1H)

CHN Analysis

Predicted: % C=74.54, % H=8.53, % N=7.90

Observed: % C=74.31, % H=8.50, % N=7.95

Example 195 Tetrahydro-2H-pyran-4-ylmethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.17-1.24 (2H), 1.40-1.48 (2H), 1.54-1.57 (3H),1.80-1.90 (1H), 2.27-2.29 (3H), 2.37-2.39 (3H), 3.20-3.30 (2H),3.79-3.84 (2H), 4.01-4.15 (2H), 5.02-5.09 (1H), 6.51-6.54 (1H),6.83-6.86 (1H), 6.95-6.98 (2H), 7.50-7.51 (1H)

Example 196 3-(3-Methoxypropoxy)propyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.95-1.04 (4H), 1.18-1.21 (3H), 1.51-1.56 (3H),2.27-2.29 (3H), 2.37-2.39 (3H), 3.20-3.23 (2H), 3.24-3.40 (3H),3.40-3.59 (2H), 5.04-5.10 (2H), 6.49-6.59 (1H), 6.82-6.88 (1H),6.96-6.99 (2H), 7.46-7.48 (1H)

Example 197 (2-Methylcyclopropyl)methyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.21-0.26 (1H), 0.40-0.48 (1H), 0.62-0.81 (2H),0.92-0.97 (3H), 1.53-1.56 (3H), 2.26-2.28 (3H), 2.37-2.39 (3H),4.00-4.12 (2H), 5.05-5.10 (1H), 6.56-6.59 (1H), 6.86-6.89 (1H),6.95-6.98 (2H), 7.50-7.51 (1H)

Example 198 3-[3-(3-Butoxypropoxy)propoxy]propyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.15-1.20 (3H), 1.30-1.40 (2H), 1.41-1.50 (2H),1.53-1.56 (3H), 2.25-2.29 (3H), 2.33-2.37 (3H), 3.20-3.25 (1H),3.30-3.41 (4H), 3.47-3.61 (5H), 5.00-5.05 (1H), 5.10-5.17 (2H),6.50-6.54 (1H), 6.82-6.86 (1H), 6.95-6.98 (2H), 7.50-7.53 (1H)

Example 199 2,2,2-Trifluoroethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.53-1.56 (3H), 2.26-2.28 (3H), 2.36-2.38 (3H),4.80-4.91 (2H), 5.05-5.10 (1H), 6.56-6.59 (1H), 6.86-6.88 (1H),6.96-6.98 (1H), 7.00-7.01 (1H), 7.50-7.51 (1H)

Example 200 Cyclobutylmethyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.55 (3H), 1.70-1.80 (2H), 1.80-1.90 (2H),1.90-2.02 (2H), 2.25-2.27 (3H), 2.35-2.37 (3H), 4.12-4.21 (2H),5.03-5.09 (1H), 6.53-6.57 (1H), 6.85-6.89 (1H), 6.95-6.98 (2H),7.46-7.47 (1H)

Example 201 (1-Methylcyclopropyl)methyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.30-0.40 (2H), 0.45-0.55 (2H), 1.02-1.05 (3H),1.53-1.56 (3H), 2.23-2.25 (3H), 2.34-2.36 (3H), 4.00-4.07 (2H),5.10-5.15 (1H), 6.57-6.59 (1H), 6.84-6.86 (1H), 6.95-6.98 (2H),7.51-7.53 (1H)

Example 202 2-Cyclopropylethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.00-0.05 (2H), 0.35-0.40 (2H), 0.60-0.68 (1H),1.45-1.56 (5H), 2.24-2.26 (3H), 2.35-2.38 (3H), 4.20-4.35 (2H),5.05-5.13 (1H), 6.51-6.53 (1H), 6.84-6.88 (1H), 6.92-6.98 (2H),7.49-7.50 (1H)

Example 203 2-Methoxy-1-(methoxymethyl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.29-2.31 (3H), 2.36-2.38 (3H),3.29-3.35 (6H), 3.41-3.51 (4H), 5.05-5.12 (2H), 6.53-6.55 (1H),6.85-6.87 (1H), 6.95-6.98 (2H), 7.49-7.51 (1H)

Example 204 (3-Methyloxetan-3-yl)methyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.25-1.26 (3H), 1.55-1.58 (3H), 2.26-2.28 (3H),2.36-2.38 (3H), 4.23-4.29 (3H), 4.39-4.44 (3H), 5.05-5.10 (1H),6.58-6.60 (1H), 6.84-6.87 (1H), 6.95-6.98 (2H), 7.50-7.52 (1H)

Example 205 5-Methylhexyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.80-0.84 (6H), 1.15-1.20 (2H), 1.25-1.30 (2H),1.49-1.61 (5H), 2.26-2.28 (3H), 2.37-2.39 (3H), 4.19-4.25 (2H),5.05-5.10 (1H), 6.56-6.58 (1H), 6.84-6.86 (1H), 6.95-6.98 (2H),7.48-7.50 (1H)

Example 206 3-(4-Fluorophenoxy)propyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.05-2.10 (2H), 2.24-2.26 (3H),2.34-2.37 (3H), 3.97-4.01 (2H), 4.36-4.40 (1H), 4.01-4.05 (1H),5.02-5.07 (1H), 6.50-6.53 (1H), 6.82-6.90 (3H), 6.91-6.96 (2H),7.00-7.05 (2H), 7.51-7.52 (1H)

CHN Analysis

Predicted: % C=69.68, % H=6.36, % N=7.07

Observed: % C=69.70, % H=6.37, % N=7.07

Example 207 2,2,3,3,3-Pentafluoropropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.53-1.57 (3H), 2.25-2.27 (3H), 2.35-2.38 (3H),4.85-4.99 (2H), 5.03-5.09 (1H), 6.55-6.58 (1H), 6.85-6.99 (2H),7.00-7.01 (1H), 7.45-7.46 (1H)

Example 208 2-(Methylthio)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.02-2.05 (3H), 2.24-2.26 (3H),2.35-2.38 (3H), 2.61-2.72 (2H), 4.30-4.41 (2H), 5.03-5.10 (1H),6.52-6.56 (1H), 6.85-6.91 (1H), 6.95-6.99 (2H), 7.50-7.51 (1H)

Example 209 Ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.17-1.21 (3H), 1.51-1.53 (3H), 2.26-2.28 (3H),2.36-2.38 (3H), 4.19-4.26 (2H), 5.03-5.08 (1H), 6.51-6.53 (1H),6.85-6.88 (1H), 6.96-6.99 (2H), 7.47-7.49 (1H)

Example 210 3-Cyclohexylpropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.79-0.89 (2H), 1.10-1.25 (6H), 1.51-1.54 (3H),1.58-1.70 (7H), 2.25-2.27 (3H), 2.35-2.38 (3H), 4.12-4.25 (2H),5.02-5.09 (1H), 6.50-6.53 (1H), 6.84-6.89 (1H), 6.95-6.98 (2H),7.49-7.54 (1H)

Example 211 3-Methylbutyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.81-0.87 (6H), 1.43-1.60 (6H), 2.27-2.29 (3H),2.36-2.38 (3H), 4.19-4.27 (2H), 5.03-5.08 (1H), 6.51-6.53 (1H),6.86-6.88 (1H), 6.96-6.99 (2H), 7.47-7.49 (1H)

Example 212 2-Isopropylcyclohexyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.50-0.54 (3H), 0.70-0.80 (3H), 1.00-1.20 (3H),1.20-1.45 (3H), 1.50-1.60 (3H), 1.61-1.72 (3H), 1.80-1.89 (1H),2.24-2.28 (3H), 2.35-2.38 (3H), 4.60-4.65 (1H), 4.70-4.76 (1H),5.00-5.08 (1H), 6.35-6.45 (1H), 6.82-6.90 (1H), 6.95-6.98 (2H),7.49-7.54 (1H)

Example 213 2-Methoxyethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.25-2.27 (3H), 2.31-2.33 (3H),3.22-3.23 (3H), 3.45-3.60 (2H), 4.30-4.40 (2H), 5.04-5.11 (1H),6.56-6.58 (1H), 6.84-6.86 (1H), 6.95-6.99 (2H), 7.44-7.45 (1H)

Example 214 Tetrahydro-2H-pyran-4-yl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.55 (3H), 1.90-1.96 (1H), 2.09-2.11 (1H),2.24-2.27 (3H), 2.32-2.34 (3H), 3.70-3.83 (4H), 5.02-5.09 (1H),5.34-5.37 (1H), 6.50-6.53 (1H), 6.83-6.86 (1H), 6.96-6.99 (2H),7.44-7.45 (1H)

Example 215 3-Cyclopentylpropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.99-1.05 (2H), 1.22-1.28 (2H), 1.48-1.62 (9H),1.69-1.74 (3H), 2.26-2.28 (3H), 2.36-2.38 (3H), 4.15-4.22 (2H),5.03-5.08 (1H), 6.51-6.53 (1H), 6.85-6.87 (1H), 6.95-6.98 (2H),7.47-7.49 (1H)

Example 216 1-Methylpiperidin-4-yl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 1.60-1.71 (3H), 1.79-1.88 (2H),2.10-2.21 (4H), 2.27-2.29 (3H), 2.36-2.38 (3H), 2.50-2.60 (2H),4.70-4.80 (1H), 5.03-5.10 (1H), 6.52-6.54 (1H), 6.82-6.88 (1H),6.95-6.98 (2H), 7.49-7.50 (1H)

Example 217 4,4,4-Trifluorobutyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.55 (3H), 1.89-1.96 (3H), 2.10-2.21 (4H),2.37-2.39 (3H), 4.21-4.26 (1H), 4.35-4.40 (1H), 5.02-5.09 (1H),6.50-6.53 (1H), 6.83-6.86 (1H), 6.96-6.99 (2H), 7.47-7.48 (1H)

Example 218 Cyclopentyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 1.55-1.75 (6H), 1.80-1.90 (2H),2.25-2.27 (3H), 2.35-2.37 (3H), 5.05-5.11 (1H), 5.18-5.20 (1H),6.52-6.54 (1H), 6.83-6.98 (3H), 7.44-7.45 (1H)

Example 219 (1-Methylcyclohexyl)methyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.92-0.93 (3H), 1.20-1.40 (5H), 1.40-1.49 (5H),1.53-1.56 (3H), 2.26-2.28 (3H), 2.36-2.38 (3H), 3.96-4.02 (2H),5.10-5.15 (1H), 6.56-6.59 (1H), 6.85-6.87 (1H), 6.95-6.98 (2H),7.48-7.50 (1H)

Example 220 Cyclopentylmethyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.17-1.25 (2H), 1.45-1.70 (11H), 2.15-2.21 (1H),2.25-2.26 (3H), 2.35-2.37 (3H), 4.04-4.19 (2H), 5.04-5.10 (1H),6.52-6.55 (1H), 6.83-6.88 (1H), 6.95-6.98 (2H), 7.47-7.48 (1H)

Example 221 4-Methylpentyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.80-0.85 (6H), 1.12-1.20 (2H), 1.50-1.56 (4H),1.58-1.61 (2H), 2.27-2.29 (3H), 2.35-2.37 (3H), 4.14-4.19 (1H),4.20-4.24 (1H), 5.04-5.08 (1H), 6.52-6.55 (1H), 6.85-6.87 (1H),6.93-6.97 (2H), 7.47-7.49 (1H)

Example 222 (1-Propylcyclobutyl)methyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.81-0.85 (3H), 1.20-1.26 (2H), 1.42-1.46 (2H),1.52-1.56 (3H), 1.75-1.86 (6H), 2.26-2.28 (3H), 2.35-2.37 (3H),4.15-4.22 (2H), 5.09-5.13 (1H), 6.58-6.60 (1H), 6.85-6.87 (1H),6.95-6.98 (2H), 7.43-7.45 (1H)

Example 223 2-[(4-Chlorophenyl)thio]ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.54-1.56 (3H), 2.25-2.27 (3H), 2.35-2.37 (3H),3.20-3.25 (2H), 4.36-4.40 (2H), 5.00-5.05 (1H), 6.51-6.53 (1H),6.85-6.87 (1H), 6.91-6.95 (2H), 7.30-7.40 (5H)

Example 224 (2S)-2-Methylbutyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.90-0.95 (3H), 1.10-1.20 (1H), 1.32-1.41 (1H),1.54-1.56 (3H), 1.65-1.71 (1H), 2.25-2.27 (3H), 2.34-2.36 (3H),4.03-4.05 (2H), 5.04-5.08 (1H), 6.52-6.54 (1H), 6.83-6.86 (1H),6.96-7.00 (2H), 7.48-7.50 (1H)

Example 225 3-(Methylthio)propyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.54 (3H), 1.85-1.92 (2H), 2.05-2.07 (3H),2.27-2.29 (3H), 2.36-2.38 (3H), 2.42-2.46 (2H), 4.22-4.30 (2H),4.23-4.29 (1H), 4.32-4.38 (1H), 6.51-6.53 (1H), 6.83-6.86 (1H),6.96-6.99 (2H), 7.51-7.53 (1H)

Example 226 Cyclohexylmethyl 2-[(1S)-1-(2,3-dimethyl phenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.82-0.99 (2H), 1.05-1.23 (3H), 1.50-1.55 (3H),1.56-1.70 (6H), 2.25-2.27 (3H), 2.37-2.39 (3H), 3.98-4.08 (2H),5.02-5.09 (1H), 6.49-6.52 (1H), 6.83-6.86 (1H), 6.96-6.99 (2H),7.48-7.49 (1H)

CHN Analysis

Predicted: % C=74.08, % H=8.29, % N=8.23

Observed: % C=74.09, % H=8.27, % N=8.27

Example 227 3-Ethoxypropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.02-1.06 (3H), 1.54-1.57 (3H), 1.80-1.86 (2H),2.26-2.28 (3H), 2.36-2.38 (3H), 3.35-3.40 (4H), 4.21-4.30 (2H),5.03-5.05 (1H), 6.52-6.54 (1H), 6.83-6.86 (1H), 6.96-6.99 (2H),7.50-7.52 (1H)

Example 228 2-Methylcyclohexyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.70-0.78 (3H), 1.00-1.10 (2H), 1.20-1.30 (2H),1.40-1.45 (1H), 1.55-1.58 (3H), 1.60-1.64 (1H), 1.65-1.75 (2H),1.80-1.85 (1H), 2.26-2.28 (3H), 2.36-2.38 (3H), 4.30-4.36 (1H),5.00-5.05 (1H), 6.40-6.44 (1H), 6.82-6.86 (1H), 6.96-6.99 (2H),7.50-7.52 (1H)

Example 229 2-(2,6-Dimethylmorpholin-4-yl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.98-1.03 (3H), 1.53-1.56 (3H), 1.59-1.65 (1H),2.21-2.24 (1H), 2.27-2.28 (3H), 2.38-2.39 (3H), 2.42-2.58 (2H),2.60-2.63 (1H), 2.65-2.67 (1H), 3.20-3.29 (1H), 3.35-3.41 (1H),4.30-4.35 (2H), 5.04-5.09 (1H), 6.54-6.56 (1H), 6.82-6.87 (1H),6.95-7.00 (2H), 7.49-7.50 (1H)

Example 230 Pentyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.81-0.86 (3H), 1.20-1.33 (4H), 1.53-1.56 (3H),1.59-1.62 (2H), 2.26-2.27 (3H), 2.35-2.36 (3H), 4.17-4.25 (2H),5.04-5.10 (1H), 6.52-6.54 (1H), 6.83-6.87 (1H), 6.95-6.97 (2H),7.49-7.50 (1H)

Example 231 trans-4-Methylcyclohexyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.82-0.90 (3H), 1.00-1.10 (1H), 1.20-1.45 (4H),1.52-1.55 (3H), 1.65-1.70 (2H), 1.85-1.95 (2H), 2.24-2.30 (6H),4.60-4.66 (1H), 5.02-5.10 (1H), 6.52-6.55 (1H), 6.82-6.98 (3H),7.46-7.49 (1H)

Example 232 2-Propylpentyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.90-0.97 (6H), 1.20-1.38 (8H), 1.54-1.58 (3H),1.65-1.72 (1H), 2.27-2.29 (3H), 2.36-2.38 (3H), 4.10-4.19 (2H),5.10-5.15 (1H), 6.55-6.58 (1H), 6.85-6.88 (1H), 6.96-6.99 (2H),7.44-7.46 (1H)

Example 233 2-Ethyl butyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.90-0.96 (6H), 1.24-1.36 (4H), 1.54-1.58 (4H),2.27-2.29 (3H), 2.36-2.38 (3H), 4.10-4.15 (1H), 4.16-4.20 (1H),5.07-5.11 (1H), 5.57-5.59 (1H), 6.83-6.87 (1H), 6.95-6.98 (2H),7.46-7.48 (1H)

Example 234 2,2-Dimethylpropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.95-0.98 (9H), 1.54-1.57 (3H), 2.26-2.28 (3H),2.32-2.34 (3H), 3.90-3.94 (1H), 3.96-4.00 (1H), 5.09-5.13 (1H),6.57-6.59 (1H), 6.84-6.88 (1H), 6.94-6.98 (2H), 7.55-7.57 (1H)

Example 235 Bicyclo[2.2.1]hept-2-ylmethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.62-0.70 (1H), 1.10-1.16 (2H), 1.25-1.35 (3H),1.40-1.48 (2H), 1.52-1.57 (3H), 1.61-1.66 (1H), 2.12-2.19 (2H),2.28-2.30 (3H), 2.37-2.39 (3H), 4.19-4.27 (2H), 5.03-5.08 (1H),6.51-6.53 (1H), 6.84-6.88 (1H), 6.96-6.99 (2H), 7.46-7.48 (1H)

Example 236 3,3-Dimethylbutyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.89-0.92 (3H), 1.48-1.57 (5H), 2.28-2.30 (3H),2.37-2.39 (3H), 4.20-4.25 (1H), 4.30-4.35 (1H), 5.02-5.08 (1H),6.51-6.53 (1H), 6.84-6.87 (1H), 6.96-6.99 (2H), 7.45-7.47 (1H)

Example 237 4-Isopropylcyclohexyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.81-0.86 (6H), 1.03-1.20 (2H), 1.20-1.29 (2H),1.38-1.48 (2H), 1.54-1.57 (3H), 1.75-1.81 (2H), 1.90-2.00 (2H),2.27-2.29 (3H), 2.37-2.39 (3H), 4.60-4.67 (1H), 5.02-5.08 (1H),6.49-6.52 (1H), 6.84-6.87 (1H), 6.96-6.99 (2H), 7.46-7.48 (1H)

CHN Analysis

Predicted: % C=74.96, % H=8.75, % N=7.60

Observed: % C=74.98, % H=8.78, % N=7.58

Example 238 3-(Ethylthio)propyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.15-1.20 (3H), 1.55-1.58 (3H), 1.83-1.89 (2H),2.28-2.30 (3H), 2.36-2.38 (3H), 2.42-2.50 (4H), 4.25-4.30 (1H),4.33-4.38 (1H), 5.04-5.08 (1H), 6.53-6.55 (1H), 6.85-6.88 (1H),6.96-6.99 (2H), 7.50-7.52 (1H)

Example 239 Propyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.82-0.86 (3H), 1.55-1.58 (3H), 1.60-1.66 (2H),2.27-2.29 (3H), 2.36-2.38 (3H), 4.10-4.20 (2H), 5.04-5.10 (1H),6.53-6.55 (1H), 6.85-6.88 (1H), 6.96-6.99 (2H), 7.49-7.51 (1H)

Example 240 3-Methoxy-3-methylbutyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.10-1.12 (6H), 1.53-1.55 (3H), 1.70-1.80 (2H),2.26-2.28 (3H), 2.37-2.38 (3H), 3.09-3.10 (3H), 4.21-4.31 (2H),5.03-5.07 (1H), 6.51-6.53 (1H), 6.85-6.88 (1H), 6.97-6.99 (2H),7.46-7.47 (1H)

Example 241 3-(Dimethylamino)-2,2-dimethylpropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.83-0.90 (6H), 1.52-1.55 (3H), 2.15-2.20 (6H),2.23-2.24 (3H), 2.35-2.36 (3H), 4.00-4.08 (2H), 5.10-5.16 (1H),6.52-6.55 (1H), 6.83-6.87 (1H), 6.95-6.99 (2H), 7.49-7.50 (1H)

Example 242 4-Methoxybutyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.47-1.55 (5H), 1.61-1.66 (2H), 2.28-2.30 (3H),2.37-2.39 (3H), 3.21-3.22 (3H), 3.30-3.34 (2H), 4.20-4.26 (2H),5.04-5.08 (1H), 6.52-6.54 (1H), 6.83-6.86 (1H), 6.97-7.00 (2H),7.48-7.49 (1H)

Example 243 2,2,4-Trimethylpentyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.82-0.90 (6H), 0.95-0.97 (6H), 1.20-1.22 (2H),1.53-1.57 (3H), 1.61-1.71 (1H), 2.25-2.27 (3H), 2.35-2.37 (3H),3.95-4.01 (2H), 5.10-5.15 (1H), 6.55-6.58 (1H), 6.84-6.87 (1H),6.95-7.00 (2H), 7.49-7.50 (1H)

CHN Analysis

Predicted: % C=74.12, % H=9.05, % N=7.86

Observed: % C=74.22, % H=9.05, % N=7.91

Example 244 Butyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.82-0.88 (3H), 1.21-1.28 (2H), 1.54-1.60 (5H),2.28-2.30 (3H), 2.37-2.39 (3H), 4.17-4.25 (2H), 5.03-5.07 (1H),6.52-6.54 (1H), 6.82-6.85 (1H), 6.97-7.00 (2H), 7.47-7.49 (1H)

Example 245 3-Fluoro-3-methylbutyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.30-1.33 (3H), 1.37-1.39 (3H), 1.53-1.56 (3H),1.85-1.95 (2H), 2.29-2.31 (3H), 2.36-2.38 (3H), 4.30-4.34 (1H),4.39-5.02 (1H), 5.03-5.07 (1H), 6.52-6.54 (1H), 6.85-6.88 (1H),6.96-6.99 (2H), 7.45-7.46 (1H)

Example 246 2-Isobutoxyethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.80-0.85 (6H), 1.53-1.57 (3H), 1.65-1.79 (1H),2.26-2.28 (3H), 2.35-2.37 (3H), 3.15-3.20 (2H), 3.57-3.64 (1H),4.31-4.40 (2H), 5.06-5.15 (1H), 6.57-6.60 (1H), 6.84-6.87 (1H),6.95-6.99 (2H), 7.47-7.48 (1H)

Example 247 4-Cyclohexylbutyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.80-0.90 (2H), 1.10-1.25 (8H), 1.50-1.70 (10H),2.27-2.29 (3H), 2.37-2.39 (3H), 4.15-4.26 (2H), 5.02-5.10 (1H),6.50-6.52 (1H), 6.84-6.87 (1H), 6.96-7.00 (2H), 7.47-7.48 (1H)

Example 248 4-Methylpent-3-en-1-yl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.60 (6H), 1.62-1.64 (3H), 2.28-2.30 (3H),2.25-2.35 (2H), 2.37-2.39 (3H), 4.11-4.21 (2H), 5.02-5.10 (2H),6.53-6.57 (1H), 6.84-6.89 (1H), 6.96-6.99 (2H), 7.42-7.43 (1H)

Example 249 1-Ethylpropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.72-0.78 (3H), 1.44-1.53 (7H), 2.25-2.28 (3H),2.32-2.35 (3H), 4.74-4.79 (1H), 5.01-5.06 (1H), 6.42-6.44 (1H),6.82-6.86 (1H), 6.96-6.99 (2H), 7.50-7.52 (1H)

Example 250 (1S)-1-Methylbutyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.89-0.93 (3H), 1.10-1.22 (5H), 1.41-1.52 (5H),2.25-2.28 (3H), 2.36-2.39 (3H), 4.89-4.95 (1H), 5.01-5.06 (1H),6.41-6.46 (1H), 6.85-6.90 (1H), 6.96-6.99 (2H), 7.47-7.49 (1H)

Example 251 (3S)-3,7-Dimethyloctyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.91-0.96 (3H), 1.10-1.16 (3H), 1.20-1.30 (3H),1.38-1.43 (1H), 1.45-1.55 (5H), 1.60-1.65 (1H), 2.29-2.31 (3H),2.36-2.38 (3H), 4.20-4.30 (2H), 5.05-5.10 (1H), 6.51-6.53 (1H),6.83-6.85 (1H), 6.96-6.98 (2H), 7.46-7.48 (1H)

Example 252 2-Propoxyethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.90-0.95 (3H), 1.42-1.52 (5H), 2.27-2.29 (3H),2.36-2.38 (3H), 3.31-3.37 (2H), 3.59-3.64 (2H), 4.30-4.36 (2H),5.07-5.12 (1H), 6.57-6.59 (1H), 6.83-6.85 (1H), 6.95-6.98 (2H),7.46-7.48 (1H)

Example 253 2,3-Dimethyl pentyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.75-0.88 (6H), 1.10-1.21 (1H), 1.30-1.43 (2H),1.52-1.55 (3H), 1.79-1.88 (1H), 2.25-2.27 (3H), 2.34-2.36 (3H),4.00-4.25 (2H), 5.02-5.11 (1H), 6.50-6.52 (1H), 6.84-6.87 (1H),6.96-6.99 (2H), 7.44-7.46 (1H)

Example 254 2,2-Dimethylbutyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.79-0.83 (3H), 0.90-0.92 (6H), 1.25-1.33 (2H),1.52-1.55 (3H), 2.24-2.26 (3H), 2.33-2.35 (3H), 3.90-3.95 (1H),4.00-4.04 (1H), 5.10-5.15 (1H), 6.57-6.59 (1H), 6.85-6.88 (1H),6.94-6.97 (2H), 7.49-7.50 (1H)

Example 255 3-Methoxy-2,2-dimethyl-3-oxopropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.19-1.24 (6H), 1.51-1.54 (3H), 2.23-2.26 (3H),2.31-2.34 (3H), 3.59-3.60 (3H), 4.20-4.30 (2H), 5.05-5.11 (1H),6.57-6.60 (1H), 6.82-6.86 (1H), 6.95-6.99 (2H), 7.19-7.20 (1H)

Example 256 4-Butoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

To a mixture of the compound of Example 58 (200 mg, 1.0 mmol) andpyridine (177 μl, 2.2 mmol) in anhydrous acetonitrile (3 ml), at 0° C.and under nitrogen, was added diphosgene (132 μl, 1.1 mmol). The mixturewas allowed to warm to room temperature and stirred for 10 min, beforeaddition to (4-butoxyphenyl)methanol (198 mg, 1.1 mmol) via syringe. Thereaction mixture was stirred at room temperature for 30 min andfiltered.

The filtrate was purified by automated preparative liquid chromatography(Gilson system, 150 mm×22.4 mm LUNA C18(2) 10 μm column, 24 ml/min)using an acetonitrile:water gradient [15:85 (3 min) to 98:2 (16 min)].The appropriate fractions were combined and concentrated to give thetitle compound (6 mg).

Experimental MH⁺ 364.0; expected 363.2 (compound de-carboxylates) ¹H-NMR(d₆-Acetone): 0.92-0.98 (3H), 1.43-1.55 (5H), 1.69-1.78 (2H), 2.24-2.30(6H), 3.97-4.01 (2H), 5.04-5.09 (1H), 5.17-5.18 (2H), 6.48-6.50 (1H),6.83-6.88 (3H), 6.95-6.98 (2H), 7.10-7.13 (2H), 7.44-7.45 (1H) Rhip.Funct. ED₁₀₀ mg/cm²=0.03

Similarly prepared from Example 58 were:

Rhip. MH⁺ Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor Expected mg/cm² 257

Biphenyl-4-ylmethanol 412.1 411.2 <=10 258

2,2-Diphenylethanol 426.0 425.0 <=10 259

(3,5-Difluorophenyl)methanol 371.2 371.2 0.1 260

(4-Chlorophenyl)methanol 369.8 369.1 >0.03 261

{4-[(4-Fluorobenzyl)oxy]- phenyl}methanol 460.0 459.2 <=10 262

(2,4,5-Trimethylphenyl)- methanol 334.0 333.2 decar- boxylates >0.03 263

(2,4-Dimethylphenyl)- methanol 363.9 363.2 >0.03 264

1-Naphthylmethanol 342.1 341.2 decar- boxylates 0.03 265

Mesitylmethanol 334.0 333.2 decar- boxylates <=10 266

[4-(1H-1,2,4-Triazol-1-yl)- phenyl]methanol — >0.03 267

(4-tert-Butylphenyl)methanol 348.1 347.2 decar- boxylates <=10 268

(2-Fluorophenyl)methanol 310.0 309.2 decar- boxylates 0.01 269

[4-(Benzyloxy)phenyl] methanol — <=10 270

(Pentafluorophenyl)- methanol 423.0 423.1 <=10 271

Biphenyl-2-ylmethanol — <=10 272

(3-Phenoxyphenyl)methanol 384.0 383.2 decar- boxylates <=10 273

(2,3,5-Trifluorophenyl)- methanol 389.9 389.1 >0.03 274

(2-Chloro-4-fluorophenyl)- methanol — >0.03 275

(4-Fluoro-3-methoxyphenyl)- methanol 383.9 383.2 >0.03 276

(2,6-Dichlorophenyl)- methanol 403.9 403.1 >0.03 277

2-(4-tert-Butylphenyl)- ethanol 406.0 405.3 >0.03 278

(2R)-2-Phenylpropan-1-ol 363.9 363.2 279

2-Mesitylethanol 392.0 391.2 >0.03 280

2-(4-Chlorophenyl)ethanol 383.9 383.2 0.03 281

2-(4-Isopropyl-2-methyl- phenyl)ethanol 406.0 405.3 <=10 282

2-(4-Methylphenyl)ethanol 364.0 363.2 <=10 283

(1S)-1-Phenylpropan-1-ol 363.9 363.2 <=10 284

2-(2,5-Dimethylphenyl)- ethanol 377.2 377.2 0.1 285

3-Phenylpropan-1-ol 363.9 363.2 >0.03 286

(2S)-2-Phenylpropan-1-ol 363.2 363.2 0.03 287

2-(3-Methylphenyl)- ethanol 363.9 363.2 >0.03 288

2-Phenylethanol 349.9 349.2 <=10 289

2-(2-Methylphenyl)- ethanol 363.2 363.2 0.03 290

2-[2-(2-Chloropyrimidin-4- yl)phenyl]ethanol — <=10 291

(2,3,4-Trifluorophenyl)- methanol 389.1 389.1 0.03 292

[2-(2-Phenylethyl)phenyl]- methanol 396.1 395.2 decar- boxylates >0.03293

(5-Fluoro-2-methylphenyl)- methanol 324.1 323.2 decar- boxylates >0.03294

(Pentamethylphenyl)- methanol — >0.03 295

[4-(Benzyloxy)-3-methoxy- phenyl]methanol 428.1 427.2 decar-boxylates >0.03 296

(2-Chlorophenyl)- methanol 326.0 325.1 decar- boxylates >0.03 297

(2-Methoxy-5- methylphenyl)-methanol 336.1 335.2 decar- boxylates <=10298

(3-Fluorophenyl)methanol 310.0 309.2 decar- boxylates >0.03 299

(4-Ethoxyphenyl)methanol 336.0 335.2 decar- boxylates <=10 300

(2,4-Difluorophenyl)methanol — >0.03 301

(2,4-Dimethoxy-3-methyl- phenyl)methanol 366.0 365.2 decar- boxylates<=10 302

(2-Fluoro-5- methoxyphenyl)methanol 339.2 339.2 decar- boxylates >0.03303

(4-Fluoro-2-methoxyphenyl)- methanol 340.0 339.2 decar- boxylates >0.03304

(4-Chloro-2-fluorophenyl)- methanol — <=10 305

(2,5-Dimethoxyphenyl)- methanol — <=10 306

(3-Ethoxyphenyl)methanol 335.9 335.2 decar- boxylates >0.03 307

(2,5-Dichlorophenyl)- methanol 359.9 359.1 decar- boxylates >0.03 308

(2,6-Difluorophenyl)methanol 328.0 327.2 decar- boxylates >0.03 309

(3,5-Dichlorophenyl)- methanol 359.9 359.1 decar- boxylates >0.03 310

(5-Chloro-2-methoxyphenyl)- methanol 355.9 355.1 decar- boxylates >0.03311

(3,4-Dimethylphenyl)- methanol 319.9 319.2 decar- boxylates >0.03 312

(4-Bromophenyl)methanol 369.9 369.1 decar- boxylates <=10 313

[4-(Cyclopentyloxy)-3- methoxyphenyl]methanol 406.1 405.2 decar-boxylates <=10 314

(2,3,5,6-Tetrafluorophenyl)- methanol 408.0 407.1 decar- boxylates >0.03315

(3-Methoxy-4-methylphenyl)- methanol 380.0 379.2 <=10 316

(4-Methylphenyl)methanol 305.8 305.2 decar- boxylates >0.03 317

4-(Hydroxymethyl)- benzonitrile 361.0 360.2 <=10 318

(2-Ethoxyphenyl)methanol 380.1 379.2 <=10 319

(2-Fluoro-5-methylphenyl)- methanol 324.0 323.2 decar- boxylates <=10320

(2,5-Difluoro-4-methyl- phenyl)methanol 385.2 385.2 <=0.03 321

(2,3,6-Trifluorophenyl)- methanol 389.9 389.1 >0.03 322

(2-Methylbiphenyl-3-yl)- methanol 426.0 425.2 <=10 323

(2-Methoxyphenyl)methanol 322.0 321.2 decar- boxylates <=0.03 324

(4-Bromo-2-fluorophenyl)- methanol 431.9 431.1 >0.03 325

(2,3-Dimethoxyphenyl)- methanol 396.0 395.2 >0.03 326

(2,3-Dichlorophenyl)- methanol 403.9 403.1 >0.03 327

(4-Butylphenyl)methanol 392.1 391.2 <=10 328

(3-Methoxyphenyl)methanol 365.9 365.2 <=10 329

(3,4-Dichlorophenyl)- methanol 403.9 403.1 >0.03 330

(3,4-Diethoxyphenyl)- methanol 380.1 379.2 decar- boxylates <=10 331

(3-Methylphenyl)methanol 350.1 349.2 >0.03 332

(4-Isopropylphenyl)methanol 378.0 377.2 >0.03 333

(3-Chlorophenyl)methanol 369.9 369.1 >0.03 334

(3,4-Difluorophenyl)methanol 327.8 327.2 decar- boxylates >0.03 335

(2-Chloro-3,4-dimethoxy- phenyl)methanol 385.9 485.2 decar-boxylates >0.03 336

(2-Methylphenyl)methanol 349.9 349.1 >0.03 337

(2-Chloro-6-fluorophenyl)- methanol 387.1 387.1 <=0.03 338

(4-Methoxyphenyl)methanol 321.9 321.2 decar- boxylates <=10 339

(2,3,5,6-Tetramethylphenyl)- methanol 391.1 391.2 <=10 340

(3,4,5-Trifluorophenyl)- methanol 345.1 345.1 decar- boxylates >0.03 341

(2,5-Difluorophenyl)methanol 327.1 327.2 decar- boxylates >0.03 342

(3,5-Dimethylphenyl)- methanol 319.1 319.2 decar- boxylates >0.03 343

[4-(1H-Pyrazol-1-yl)phenyl]- methanol — <=10 344

(3-Chloro-4-methylphenyl)- methanol 340.0 339.2 decar- boxylates >0.03345

(4-Ethoxy-3-methoxyphenyl)- methanol 365.1 365.2 decar- boxylates >0.03346

3-(Hydroxymethyl)- benzonitrile 360.1 360.2 <=10 347

(2-Methoxy-4-methylphenyl)- methanol 335.2 335.2 decar- boxylates >0.03348

(4-Fluorophenyl)methanol 309.1 309.2 decar- boxylates <=0.03

Example 257 Biphenyl-4-ylmethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.23-2.30 (6H), 5.09-5.13 (1H),5.29-5.32 (2H), 6.50-6.52 (1H), 6.84-6.86 (1H), 6.96-6.99 (2H),7.35-7.39 (3H), 7.42-7.46 (2H), 7.57-7.58 (1H), 7.60-7.68 (4H)

Example 258 2,2-Diphenylethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.48-1.56 (3H), 2.25-2.35 (6H), 4.40-4.47 (1H),4.79-4.87 (2H), 5.00-5.05 (1H), 6.55-6.58 (1H), 6.82-6.88 (2H),6.95-6.99 (1H), 7.19-7.21 (1H), 7.21-7.24 (2H), 7.29-7.39 (8H)

Example 259 3,5-Difluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.56 (3H), 2.22-2.24 (3H), 2.28-2.30 (3H),5.02-5.10 (1H), 5.22-5.25 (1H), 5.32-5.37 (1H), 6.48-6.50 (1H),6.84-7.00 (6H), 7.59-7.60 (1H)

Example 260 4-Chlorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.53-1.56 (3H), 2.22-2.28 (6H), 5.02-5.07 (1H),5.21-5.28 (2H), 6.48-6.51 (1H), 6.84-6.87 (1H), 6.97-6.99 (2H),7.25-7.28 (2H), 7.36-7.39 (2H), 7.50-7.51 (1H)

Example 261 4-[(4-Fluorobenzyl)oxy]benzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.22-2.30 (6H), 5.04-5.13 (3H),5.19-5.20 (2H), 6.51-6.53 (1H), 6.82-6.86 (1H), 6.95-7.00 (4H),7.11-7.20 (2H), 7.22-7.25 (2H), 7.45-7.46 (1H), 7.50-7.56 (2H)

Example 262 2,4,5-Trimethylbenzyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.15-2.17 (3H), 2.19-2.23 (6H),2.23-2.25 (3H), 5.02-5.06 (1H), 5.17-5.20 (1H), 5.21-5.24 (1H),6.48-6.51 (1H), 6.84-6.86 (1H), 6.96-6.99 (3H), 7.00-7.01 (1H),7.46-7.48 (1H)

Example 263 2,4-dimethylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate Example264 1-Naphthylmethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.46-1.51 (3H), 2.19-2.26 (6H), 5.04-5.10 (1H),5.75-5.79 (2H), 6.52-6.55 (1H), 6.83-6.87 (1H), 6.90-6.96 (2H),7.42-7.50 (3H), 7.53-7.58 (2H), 7.95-7.99 (2H), 8.00-8.03 (1H)

Example 265 Mesitylmethyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate Example 266 4-(1H-1,2,4-Triazol-1-yl)benzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.53-1.56 (3H), 2.22-2.24 (3H), 2.30-2.32 (3H),5.03-5.08 (1H), 5.31-5.39 (2H), 6.49-6.52 (1H), 6.84-6.86 (1H),6.97-7.00 (2H), 7.41-7.44 (2H), 7.56-7.58 (1H), 7.80-7.83 (2H),8.13-8.14 (1H), 9.02-9.04 (1H)

Example 267 4-tert-Butylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.28-1.33 (9H), 1.52-1.55 (3H), 2.22-2.28 (6H),5.02-5.07 (1H), 5.20-5.22 (2H), 6.51-6.53 (1H), 6.84-6.86 (1H),6.95-6.98 (2H), 7.20-7.23 (2H), 7.38-7.41 (2H), 7.50-7.51 (1H)

Example 268 2-Fluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 2.22-2.28 (6H), 5.02-5.07 (1H),5.28-5.31 (1H), 5.37-5.40 (1H), 6.51-6.53 (1H), 6.83-6.85 (1H),6.95-6.98 (2H), 7.16-7.20 (2H), 7.30-7.33 (1H), 7.40-7.43 (1H),7.46-7.47 (1H)

Example 269 4-(Benzyloxy)benzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.24-2.29 (6H), 5.02-5.07 (1H),5.11-5.13 (2H), 5.18-5.20 (2H), 6.48-6.50 (1H), 6.81-6.84 (1H),6.94-7.00 (4H), 7.20-7.24 (2H), 7.33-7.41 (3H), 7.42-7.45 (3H)

Example 270 Pentafluorobenzyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.25-2.27 (3H), 2.29-2.31 (3H),4.99-5.02 (1H), 5.38-5.41 (1H), 5.42-5.45 (1H), 6.40-6.42 (1H),6.80-6.83 (1H), 6.90-6.92 (1H), 6.97-6.98 (1H), 7.46-7.47 (1H)

Example 271 Biphenyl-2-ylmethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.15-2.17 (3H), 2.19-2.21 (3H),4.98-5.02 (1H), 5.19-5.21 (2H), 6.48-6.50 (1H), 6.85-6.95 (3H),7.20-7.24 (2H), 7.30-7.38 (5H), 7.39-7.41 (2H), 7.41-7.44 (1H)

Example 272 3-Phenoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.54-1.57 (3H), 2.23-2.25 (3H), 2.28-2.30 (3H),5.02-5.10 (1H), 5.20-5.27 (2H), 6.51-6.54 (1H), 6.83-6.85 (1H),6.91-7.04 (7H), 7.13-7.17 (1H), 7.30-7.41 (3H), 7.49-7.50 (1H)

Example 273 2,3,5-Trifluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.53-1.56 (3H), 2.22-2.25 (3H), 2.29-2.32 (3H),5.00-5.05 (1H), 5.30-5.33 (1H), 5.40-5.43 (1H), 6.48-6.50 (1H),6.82-6.85 (1H), 6.93-6.98 (3H), 7.25-7.29 (1H), 7.57-7.59 (1H)

Example 274 2-Chloro-4-fluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.21-2.27 (6H), 5.02-5.06 (1H),5.30-5.34 (1H), 5.36-5.40 (1H), 6.49-6.51 (1H), 6.84-6.86 (1H),6.95-6.98 (2H), 7.09-7.12 (1H), 7.32-7.34 (1H), 7.39-7.41 (1H),7.49-7.51 (1H)

Example 275 4-Fluoro-3-methoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.01-2.03 (3H), 2.21-2.26 (6H),3.80-3.81 (3H), 5.05-5.10 (1H), 5.20-5.23 (2H), 6.47-6.49 (1H),6.84-6.87 (2H), 6.95-6.98 (2H), 7.09-7.16 (2H), 7.49-7.51 (1H)

Example 276 2,6-Dichlorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.20-2.26 (6H), 5.00-5.05 (1H),5.70-5.72 (1H), 5.77-5.79 (1H), 6.47-6.49 (1H), 6.81-6.83 (1H),6.95-6.98 (2H), 7.42-7.43 (1H), 7.49-7.52 (3H)

Example 277 2-(4-tert-Butylphenyl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.23-1.27 (9H), 1.50-1.53 (3H), 2.23-2.30 (6H),2.85-2.93 (2H), 4.38-4.42 (2H), 5.00-5.05 (1H), 6.54-6.56 (1H),6.85-6.88 (1H), 6.91-6.95 (2H), 7.16-7.19 (2H), 7.35-7.38 (2H),7.42-7.43 (1H)

Example 278 (2R)-2-Phenylpropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.22-1.26 (3H), 1.50-1.53 (3H), 2.25-2.27 (3H),2.30-2.32 (3H), 3.12-3.18 (1H), 4.24-4.30 (2H), 5.00-5.06 (1H),6.52-6.54 (1H), 6.85-6.90 (2H), 6.90-6.94 (1H), 7.20-7.25 (3H),7.29-7.32 (2H), 7.37-7.39 (1H)

Example 279 2-Mesitylethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.53-1.55 (3H), 2.20-2.21 (3H), 2.24-2.26 (6H),2.27-2.29 (3H), 2.36-2.38 (3H), 4.20-4.25 (2H), 5.01-5.06 (1H),6.51-6.53 (1H), 6.80-6.81 (2H), 6.85-6.87 (1H), 6.95-6.99 (2H),7.46-7.48 (1H)

Example 280 2-(4-Chlorophenyl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.24-2.26 (3H), 2.26-2.28 (3H),2.90-2.96 (2H), 4.40-4.50 (2H), 5.01-5.06 (1H), 6.52-6.54 (1H),6.83-6.96 (3H), 7.20-7.23 (2H), 7.25-7.27 (2H), 7.39-7.40 (1H)

Example 281 2-(4-Isopropyl-2-methylphenyl)ethyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.19-1.26 (9H), 1.50-1.55 (3H), 2.25-2.29 (6H),2.85-2.92 (1H), 3.04-3.15 (1H), 4.22-4.31 (2H), 5.00-5.10 (1H),6.52-6.55 (1H), 6.82-6.96 (3H), 7.15-7.21 (4H), 7.38-7.39 (1H)

Example 282 2-(4-Methylphenyl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.25-2.28 (6H), 2.30-2.31 (3H),2.84-2.89 (2H), 4.35-4.42 (2H), 5.01-5.09 (1H), 6.53-6.55 (1H),6.82-6.87 (1H), 6.95-6.98 (2H), 7.08-7.09 (4H), 7.40-7.41 (1H)

Example 283 1-Phenylpropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.89-0.93 (3H), 1.54-1.57 (3H), 1.79-1.84 (1H),1.90-2.00 (1H), 2.30-2.36 (6H), 5.00-5.05 (1H), 5.60-5.64 (1H),6.47-6.49 (1H), 6.89-6.93 (1H), 6.98-7.02 (2H), 7.19-7.21 (2H),7.29-7.33 (3H), 7.60-7.61 (1H)

Example 284 2-(2,5-Dimethylphenyl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.56 (3H), 2.20-2.25 (6H), 2.29-2.36 (6H),2.81-2.94 (2H), 4.31-4.41 (2H), 5.00-5.05 (1H), 6.50-6.52 (1H),6.84-6.98 (5H), 7.00-7.02 (1H), 7.42-7.43 (1H)

Example 285 3-Phenylpropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 1.90-1.98 (2H), 2.23-2.25 (3H),2.36-2.38 (3H), 2.60-2.64 (2H), 4.20-4.26 (2H), 5.04-5.08 (1H),6.51-6.53 (1H), 6.85-6.88 (1H), 6.96-6.98 (2H), 7.16-7.19 (3H),7.22-7.25 (2H), 7.46-7.48 (1H)

Example 286 2-Phenylpropyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.20-1.24 (3H), 1.51-1.55 (3H), 2.25-2.27 (3H),2.32-2.34 (3H), 3.05-3.09 (1H), 4.25-4.39 (2H), 5.02-5.10 (1H),6.51-6.53 (1H), 6.81-6.95 (3H), 7.19-7.22 (1H), 7.27-7.30 (4H),7.37-7.38 (1H)

CHN Analysis

Predicted: % C=76.21, % H=7.23, % N=7.73

Observed: % C=76.07, % H=7.24, % N=7.63

Example 287 2-(3-Methylphenyl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.22-2.25 (6H), 2.32-2.35 (3H),4.38-4.42 (2H), 5.01-5.05 (1H), 6.55-6.57 (1H), 6.85-6.88 (1H),6.92-7.00 (3H), 7.00-7.05 (2H), 7.14-7.18 (1H), 7.40-7.41 (1H)

Example 288 2-Phenylethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.26-2.28 (3H), 2.31-2.33 (3H),2.90-2.96 (2H), 4.39-4.44 (2H), 5.02-5.06 (1H), 6.52-6.55 (1H),6.85-6.95 (3H), 7.20-7.30 (5H), 7.39-7.40 (1H)

Example 289 2-(2-Methylphenyl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.27-2.30 (6H), 2.33-2.35 (3H),2.85-2.99 (2H), 4.35-4.42 (2H), 5.02-5.09 (1H), 6.50-6.52 (1H),6.84-6.87 (1H), 6.96-6.99 (2H), 7.10-7.19 (4H), 7.41-7.42 (1H)

CHN Analysis

Predicted: % C=76.21, % H=7.23, % N=7.73

Observed: % C=76.22, % H=7.22, % N=7.66

Example 290 2-[2-(2-Chloropyrimidin-4-yl)phenyl]ethyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 2.21-2.29 (6H), 3.10-3.20 (1H),3.20-3.28 (1H), 4.40-4.50 (2H), 4.97-5.03 (1H), 6.50-6.52 (1H),6.83-6.91 (3H), 7.18-7.29 (4H), 7.35-7.38 (1H), 7.40-7.42 (1H),8.75-8.77 (1H)

Example 291 2,3,4-Trifluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.22-2.30 (6H), 5.01-5.07 (1H),5.25-5.30 (1H), 5.39-5.41 (1H), 6.42-6.44 (1H), 6.81-6.85 (1H),6.92-6.97 (2H), 7.16-7.20 (2H), 7.44-7.46 (1H)

CHN Analysis

Predicted: % C=64.94, % H=4.93, % N=7.21

Observed: % C=64.90, % H=4.93, % N=7.21

Example 292 2-(2-Phenylethyl)benzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.21-2.25 (6H), 2.80-2.85 (2H),2.90-2.95 (2H), 5.01-5.06 (1H), 5.20-5.24 (1H), 5.31-5.35 (1H),6.49-6.52 (1H), 6.82-6.85 (1H), 6.94-6.97 (2H), 7.12-7.20 (4H),7.20-7.26 (3H), 7.30-7.34 (2H), 7.46-7.47 (1H)

Example 293 5-Fluoro-2-methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.20-2.29 (9H), 5.01-5.06 (1H),5.20-5.25 (1H), 5.31-5.35 (1H), 6.48-6.51 (1H), 6.82-6.85 (1H),6.92-7.00 (2H), 7.00-7.05 (2H), 7.20-7.24 (1H), 7.56-7.58 (1H)

Example 294 Pentamethylbenzyl 2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.45-1.49 (3H), 2.00-2.02 (3H), 2.11-2.13 (6H),2.18-2.22 (9H), 2.22-2.23 (3H), 4.98-5.02 (1H), 5.31-5.35 (1H),5.40-5.43 (1H), 6.40-6.43 (1H), 6.81-6.84 (1H), 6.90-6.94 (2H),7.43-7.45 (1H)

Example 295 4-(Benzyloxy)-3-methoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.21-2.27 (6H), 3.78-3.80 (3H),5.04-5.11 (3H), 5.18-5.20 (2H), 6.50-6.53 (1H), 6.80-6.90 (2H),6.90-7.00 (4H), 7.30-7.40 (3H), 7.43-7.46 (2H)

Example 296 2-Chlorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.20-2.26 (6H), 5.04-5.09 (1H),5.30-5.40 (2H), 6.50-6.53 (1H), 6.83-6.85 (1H), 6.96-7.00 (2H),7.30-7.33 (2H), 7.39-7.41 (1H), 7.43-7.45 (1H), 7.54-7.55 (1H)

Example 297 2-Methoxy-5-methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.20-2.30 (9H), 3.78-3.80 (3H),5.04-5.12 (1H), 5.20-5.27 (2H), 6.52-6.54 (1H), 6.85-6.90 (2H),6.95-7.00 (2H), 7.00-7.02 (1H), 7.15-7.18 (1H), 7.42-7.44 (1H)

Example 298 3-Fluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.22-2.28 (6H), 5.02-5.07 (1H),5.12-5.19 (2H), 6.49-6.51 (1H), 6.82-6.84 (1H), 6.96-7.00 (2H),7.02-7.10 (3H), 7.36-7.40 (1H), 7.57-7.58 (1H)

Example 299 4-Ethoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.37-1.40 (3H), 1.50-1.53 (3H), 2.23-2.28 (6H),4.00-4.05 (2H), 5.03-5.07 (1H), 5.17-5.20 (2H), 6.49-6.51 (1H),6.82-6.90 (3H), 6.95-6.99 (2H), 7.10-7.14 (2H), 7.44-7.46 (1H)

Example 300 2,4-Difluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.22-2.27 (6H), 5.01-5.05 (1H),5.21-5.24 (1H), 5.35-5.39 (1H), 6.43-6.45 (1H), 6.91-6.93 (1H),6.95-7.00 (2H), 7.00-7.09 (2H), 7.37-7.40 (1H), 7.44-7.46 (1H)

Example 301 2,4-Dimethoxy-3-methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.57-1.60 (3H), 2.09-2.11 (3H), 2.22-2.27 (6H),3.71-3.73 (3H), 3.79-3.81 (3H), 4.45-4.54 (3H), 6.69-6.72 (1H),6.89-6.91 (2H), 6.95-7.00 (3H), 7.10-7.12 (1H)

Example 302 2-Fluoro-5-methoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.22-2.27 (6H), 3.79-3.81 (3H),5.02-5.07 (1H), 5.21-5.24 (1H), 5.26-5.29 (1H), 6.51-6.54 (1H),6.83-6.86 (1H), 6.90-6.96 (4H), 7.03-7.06 (1H), 7.49-7.51 (1H

Example 303 4-Fluoro-2-methoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.22-2.26 (6H), 3.80-3.81 (3H),5.02-5.07 (1H), 5.19-5.22 (1H), 5.23-5.26 (1H), 6.49-6.52 (1H),6.62-6.66 (1H), 6.80-6.90 (2H), 6.95-6.98 (2H), 7.21-7.24 (1H),7.42-7.44 (1H)

Example 304 4-Chloro-2-fluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.21-2.27 (6H), 5.01-5.05 (1H),5.21-5.25 (1H), 5.35-5.39 (1H), 6.47-6.50 (1H), 6.82-6.86 (1H),6.92-6.96 (2H), 7.20-7.22 (1H), 7.25-7.35 (2H), 7.47-7.49 (1H)

Example 305 2,5-Dimethoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.21-2.25 (6H), 3.72-3.76 (6H),5.05-5.09 (1H), 5.20-5.24 (2H), 6.54-6.57 (1H), 6.82-6.93 (6H),7.47-7.49 (1H)

Example 306 3-Ethoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.35-1.39 (3H), 1.52-1.55 (3H), 2.22-2.27 (6H),4.00-4.04 (2H), 5.03-5.07 (1H), 5.20-5.24 (2H), 6.51-6.53 (1H),6.80-6.89 (4H), 6.95-6.98 (2H), 7.20-7.24 (1H), 7.50-7.52 (1H)

Example 307 2,5-Dichlorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.21-2.27 (6H), 5.01-5.06 (1H),5.30-5.34 (1H), 5.39-5.43 (1H), 6.50-6.53 (1H), 6.84-6.87 (1H),6.92-6.97 (2H), 7.40-7.47 (3H), 7.48-7.50 (1H)

Example 308 2,6-Difluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.21-2.27 (6H), 5.01-5.06 (1H),5.32-5.36 (1H), 5.40-5.44 (1H), 6.50-6.53 (1H), 6.82-6.85 (1H),6.90-6.95 (2H), 7.42-7.44 (1H), 7.50-7.55 (1H)

Example 309 3,5-Dichlorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.22-2.24 (3H), 2.27-2.30 (3H),5.01-5.06 (1H), 5.20-5.24 (1H), 5.31-5.35 (1H), 6.50-6.53 (1H),6.85-6.88 (1H), 6.95-6.99 (2H), 7.29-7.31 (1H), 7.42-7.44 (1H),7.57-7.59 (1H)

Example 310 5-Chloro-2-methoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.21-2.27 (6H), 3.79-3.81 (3H),5.03-5.09 (1H), 5.20-5.23 (1H), 5.27-5.30 (1H), 6.51-6.53 (1H),6.84-6.86 (1H), 6.90-6.94 (2H), 7.00-7.03 (1H), 7.21-7.23 (1H),7.35-7.38 (1H), 7.50-7.51 (1H)

Example 311 3,4-Dimethylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.20-2.25 (6H), 2.26-2.30 (6H),5.05-5.10 (1H), 5.17-5.21 (2H), 6.50-6.53 (1H), 6.83-6.85 (1H),6.95-6.97 (2H), 6.98-7.03 (2H), 7.05-7.08 (1H), 7.44-7.46 (1H)

Example 312 4-Bromobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.22-2.29 (6H), 5.01-5.06 (1H),5.20-5.29 (2H), 6.43-6.45 (1H), 6.83-6.86 (1H), 6.95-6.99 (2H),7.09-7.11 (2H), 7.49-7.53 (3H)

Example 313 4-(Cyclopentyloxy)-3-methoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 1.58-1.62 (2H), 1.70-1.81 (4H),1.82-1.89 (2H), 2.22-2.28 (6H), 3.75-3.77 (3H), 4.80-4.83 (1H),5.06-5.10 (1H), 5.17-5.19 (2H), 6.50-6.53 (1H), 6.80-6.90 (3H),6.93-6.98 (3H), 7.47-7.48 (1H)

Example 314 2,3,5,6-Tetrafluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.22-2.28 (6H), 5.00-5.05 (1H),5.39-5.43 (1H), 5.45-5.48 (1H), 6.42-6.45 (1H), 6.80-6.83 (1H),6.89-6.91 (1H), 6.95-6.97 (1H), 7.47-7.48 (1H), 7.59-7.63 (1H)

Example 315 3-Methoxy-4-methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.07-2.09 (3H), 2.22-2.28 (6H),3.78-3.80 (3H), 5.04-5.09 (1H), 5.20-5.22 (2H), 6.50-6.53 (1H),6.78-6.80 (1H), 6.82-6.88 (2H), 6.95-6.98 (2H), 7.18-7.20 (1H),7.50-7.51 (1H)

Example 316 4-Methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.55 (3H), 2.22-2.30 (9H), 5.02-5.06 (1H),5.20-5.23 (2H), 6.50-6.53 (1H), 6.83-6.86 (1H), 6.95-6.98 (2H),7.15-7.19 (3H), 7.45-7.46 (1H)

Example 317 4-Cyanobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.21-2.28 (6H), 5.02-5.08 (1H),5.35-5.42 (2H), 6.49-6.52 (1H), 6.88-6.92 (1H), 6.97-7.00 (2H),7.40-7.43 (2H), 7.58-7.59 (1H), 7.70-7.73 (2H)

Example 318 2-Ethoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.20-1.26 (3H), 1.50-1.53 (3H), 2.20-2.24 (6H),3.97-4.03 (2H), 5.05-5.13 (1H), 5.21-5.24 (1H), 5.33-5.36 (1H),6.53-6.55 (1H), 6.82-6.89 (2H), 6.92-6.98 (3H), 7.19-7.21 (1H),7.30-7.33 (1H), 7.46-7.47 (1H)

Example 319 2-Fluoro-5-methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 2.22-2.31 (9H), 5.02-5.10 (1H),5.20-5.23 (1H), 5.31-5.34 (1H), 6.50-6.52 (1H), 6.82-6.86 (1H),6.94-6.98 (2H), 7.00-7.04 (1H), 7.10-7.13 (1H), 7.20-7.24 (1H),7.45-7.46 (1H)

Example 320 2,5-Difluoro-4-methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 2.22-2.31 (9H), 5.01-5.06 (1H),5.20-5.24 (1H), 5.30-5.33 (1H), 6.46-6.48 (1H), 6.82-6.99 (3H),7.00-7.10 (2H), 7.49-7.53 (1H)

Example 321 2,3,6-Trifluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.21-2.28 (6H), 5.01-5.06 (1H),5.35-5.39 (1H), 5.41-5.45 (1H), 6.44-6.46 (1H), 6.81-6.85 (1H),6.93-6.98 (2H), 7.05-7.08 (1H), 7.40-7.45 (2H)

Example 322 (2-Methylbiphenyl-3-yl)methyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 2.17-2.18 (3H), 2.21-2.26 (6H),5.05-5.11 (1H), 5.36-5.41 (2H), 6.50-6.52 (1H), 6.85-6.88 (1H),6.93-6.98 (2H), 7.20-7.32 (5H), 7.38-7.40 (1H), 7.41-7.45 (2H),7.56-7.57 (1H)

Example 323 2-Methoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 2.22-2.29 (6H), 3.79-3.80 (3H),5.03-5.11 (1H), 5.20-5.30 (2H), 6.51-6.53 (1H), 6.82-6.99 (4H),7.00-7.02 (1H), 7.18-7.20 (1H), 7.33-7.36 (1H), 7.45-7.46 (1H)

Example 324 4-Bromo-2-fluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.55 (3H), 2.21-2.27 (6H), 5.01-5.06 (1H),5.22-5.26 (1H), 5.32-5.36 (1H), 6.45-6.47 (1H), 6.82-6.85 (1H),6.95-6.98 (2H), 7.20-7.23 (1H), 7.35-7.38 (1H), 7.40-7.43 (1H),7.51-7.53 (1H)

Example 325 2,3-Dimethoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.22-2.27 (6H), 3.69-3.70 (3H),3.83-3.84 (3H), 5.04-5.09 (1H), 5.24-5.27 (2H), 6.51-6.53 (1H),6.79-6.81 (1H), 6.84-6.87 (1H), 6.95-6.98 (2H), 7.00-7.06 (2H),7.45-7.46 (1H)

Example 326 2,3-Dichlorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.54-1.57 (3H), 2.21-2.26 (6H), 5.02-5.08 (1H),5.35-5.40 (1H), 5.41-5.45 (1H), 6.47-6.49 (1H), 6.84-6.87 (1H),6.97-7.00 (2H), 7.21-7.23 (1H), 7.30-7.33 (1H), 7.57-7.58 (1H),7.58-7.59 (1H)

Example 327 4-Butylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 0.88-0.94 (3H), 1.30-1.40 (2H), 1.50-1.61 (5H),2.23-2.26 (6H), 2.80-2.83 (2H), 5.02-5.10 (1H), 5.20-5.21 (2H),6.50-6.52 (1H), 6.83-6.86 (1H), 6.95-6.99 (2H), 7.17-7.20 (4H),7.47-7.48 (1H)

Example 328 3-Methoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 2.22-2.27 (6H), 3.88-4.00 (3H),5.04-5.09 (1H), 5.21-5.23 (2H), 6.52-6.54 (1H), 6.81-6.90 (4H),6.95-6.99 (2H), 7.21-7.25 (1H), 7.46-7.47 (1H)

Example 329 3,4-Dichlorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.53-1.56 (3H), 2.23-2.28 (6H), 5.02-5.08 (1H),5.20-5.24 (1H), 5.27-5.31 (1H), 6.44-6.46 (1H), 6.84-6.87 (1H),6.96-6.99 (2H), 7.20-7.22 (1H), 7.50-7.56 (3H)

Example 330 3,4-Diethoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.31-1.39 (6H), 1.50-1.55 (3H), 2.22-2.28 (6H),3.96-4.07 (4H), 5.03-5.09 (1H), 5.17-5.18 (2H), 6.52-6.54 (1H),6.80-6.90 (3H), 6.95-7.00 (3H), 7.45-7.46 (1H)

Example 331 3-Methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.53-1.56 (3H), 2.23-2.30 (9H), 5.04-5.09 (1H),5.20-5.24 (2H), 6.49-6.51 (1H), 6.84-6.87 (1H), 6.95-6.98 (2H),7.05-7.10 (2H), 7.15-7.18 (1H), 7.20-7.23 (1H), 7.48-7.49 (1H)

Example 332 4-Isopropylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.20-1.24 (6H), 1.52-1.55 (3H), 2.23-2.28 (6H),5.03-5.08 (1H), 5.20-5.22 (2H), 6.49-6.51 (1H), 6.83-6.86 (1H),6.96-6.99 (2H), 7.20-7.24 (4H), 7.50-7.51 (1H)

Example 333 3-Chlorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.22-2.24 (3H), 2.27-2.29 (3H),5.02-5.07 (1H), 5.21-5.30 (2H), 6.49-6.51 (1H), 6.85-6.88 (1H),6.95-6.99 (2H), 7.20-7.22 (1H), 7.35-7.39 (3H), 7.57-7.58 (1H)

Example 334 3,4-Difluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.22-2.24 (3H), 2.28-2.30 (3H),5.02-5.07 (1H), 5.20-5.24 (1H), 5.25-5.29 (1H), 6.44-6.46 (1H),6.83-6.86 (1H), 6.95-6.99 (2H), 7.09-7.12 (1H), 7.21-7.28 (2H),7.56-7.57 (1H)

Example 335 2-Chloro-3,4-dimethoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.22-2.26 (6H), 3.80-3.81 (3H),3.90-3.92 (3H), 5.02-5.06 (1H), 5.21-5.29 (2H), 6.49-6.51 (1H),6.85-6.89 (1H), 6.94-7.00 (3H), 7.09-7.12 (1H), 7.44-7.46 (1H)

Example 336 2-Methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.20-2.29 (9H), 5.02-5.07 (1H),5.21-5.25 (1H), 5.29-5.34 (1H), 6.48-6.51 (1H), 6.84-6.89 (2H),6.90-6.96 (2H), 7.16-7.25 (3H), 7.50-7.51 (1H)

Example 337 2-Chloro-6-fluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 2.21-2.25 (6H), 5.01-5.06 (1H),5.39-5.67 (2H), 6.49-6.52 (1H), 6.82-6.87 (1H), 6.90-6.95 (2H),7.19-7.24 (1H), 7.35-7.38 (1H), 7.43-7.44 (1H), 7.50-7.56 (1H)

Example 338 4-Methoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 2.24-2.29 (6H), 3.80-3.81 (3H),5.02-5.10 (1H), 5.19-5.20 (2H), 6.50-6.53 (1H), 6.83-6.90 (3H),6.95-6.99 (2H), 7.20-7.23 (2H), 7.43-7.44 (1H)

Example 339 2,3,5,6-Tetramethylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.44-1.47 (3H), 2.02-2.06 (3H), 2.09-2.12 (6H),2.19-2.23 (9H), 4.98-5.03 (1H), 5.33-5.35 (1H), 5.30-5.03 (1H),6.40-6.42 (1H), 6.80-6.84 (1H), 6.90-6.94 (2H), 7.00-7.01 (1H),7.43-7.44 (1H)

Example 340 3,4,5-Trifluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.54 (3H), 2.22-2.24 (3H), 2.29-2.31 (3H),5.02-5.08 (1H), 5.20-5.24 (1H), 5.30-5.34 (1H), 6.45-6.47 (1H),6.83-6.86 (1H), 6.93-6.97 (2H), 7.10-7.16 (2H), 7.57-7.58 (1H)

Example 341 2,5-Difluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.22-2.28 (6H), 5.02-5.09 (1H),5.23-5.26 (1H), 5.36-5.40 (1H), 6.50-6.52 (1H), 6.82-6.86 (1H),6.92-6.96 (2H), 7.05-7.10 (1H), 7.19-7.23 (2H), 7.51-7.52 (1H)

Example 342 3,5-Dimethylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.22-2.31 (12H), 5.05-5.15 (1H),5.18-5.20 (2H), 6.52-6.54 (1H), 6.87-6.90 (3H), 6.95-6.98 (3H),7.50-7.51 (1H)

Example 343 4-(1H-Pyrazol-1-yl)benzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.22-2.28 (6H), 5.05-5.14 (1H),5.25-5.31 (2H), 6.43-6.45 (2H), 6.83-6.86 (1H), 6.96-6.99 (2H),7.39-7.42 (2H), 7.53-7.54 (1H), 7.69-7.70 (1H), 7.80-7.83 (2H),8.35-8.36 (1H)

Example 344 3-Chloro-4-methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.21-2.33 (9H), 5.02-5.10 (1H),5.20-5.27 (2H), 6.47-6.49 (1H), 6.83-6.86 (1H), 6.94-6.97 (2H),7.10-7.21 (2H), 7.33-7.36 (1H), 7.51-7.53 (1H)

Example 345 4-Ethoxy-3-methoxybenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate Example346 3-Cyanobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.22-2.28 (6H), 5.02-5.09 (1H),5.28-5.31 (1H), 5.38-5.41 (1H), 6.43-6.45 (1H), 6.84-6.86 (1H),6.95-6.98 (2H), 7.55-7.60 (3H), 7.61-7.63 (1H), 7.85-7.88 (1H)

Example 347 2-Methoxy-4-methylbenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.53 (3H), 2.21-2.25 (6H), 2.32-2.34 (3H),3.78-3.79 (3H), 5.06-5.11 (1H), 5.19-5.25 (2H), 6.50-6.53 (1H),6.72-6.74 (1H), 6.81-6.90 (2H), 6.93-6.97 (2H), 7.05-6.08 (1H),7.42-7.43 (1H)

Example 348 4-Fluorobenzyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.50-1.54 (3H), 2.23-2.27 (6H), 5.01-5.06 (1H),5.21-5.29 (2H), 6.47-6.49 (1H), 6.82-6.85 (1H), 6.95-6.98 (2H),7.05-7.11 (2H), 7.32-7.38 (2H), 7.48-7.50 (1H)

Example 349 (7-Methoxy-1,3-benzodioxol-5-yl)methyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

To a mixture of the compound of Example 1 (180 mg, 0.90 mmol) andpyridine (146 μl, 1.80 mmol) in anhydrous acetonitrile (3 ml), at 0° C.and under nitrogen, was added diphosgene (54 μl, 89 mg, 0.45 mmol). Themixture was allowed to warm to room temperature and stirred for 10 min,before addition of (7-methoxy-1,3-benzodioxol-5-yl)methanol (137 mg,0.75 mmol) in acetonitrile (1 ml), via syringe. The reaction mixture wasstirred at room temperature for 30 min and then filtered.

The filtrate was purified by automated preparative liquid chromatography(Gilson system, 150 mm×22.4 mm LUNA C18(2) 5 μm column, 20 ml/min) usingan acetonitrile:water gradient [15:85 to 98:2]. The appropriatefractions were combined and concentrated to give the title compound (20mg).

Experimental MH⁺ 365.9 (minus 44); expected 409.2 or 365.2 ¹H-NMR(d₆-Acetone): 1.50-1.54 (3H), 2.24-2.32 (6H), 3.80-3.81 (3H), 5.05-5.12(1H), 5.15-5.18 (2H), 6.00-6.01 (2H), 6.50-6.53 (2H), 6.63-6.64 (1H),6.82-6.86 (1H), 6.95-6.97 (2H), 7.49-7.50 (1H)

Rhip. Funct. ED₁₀₀ mg/cm²=0.03

Similarly prepared from Example 58 were:

Rhip. MH⁺ Funct. Ex. Found/ ED₁₀₀ No. R⁶ Precursor Expected mg/cm² 350

2-Naphthylmethanol 385.9 385.2 <=10 351

(4-Phenyl-2-furyl)- methanol — >0.03 352

(6-Phenoxypyridin-3-yl)- methanol 428.9 428.2 <=10 353

5-(6-Fluoro-1H-indol-1- yl)pentan-1-ol 449.0 448.2 >0.03 354

2-(6-Methoxy-1,5- naphthyridin-4-yl)- ethanol 432.0 431.2 <=10 355

2-(2-Naphthyl)ethanol 399.9 399.2 <=10 356

1-Benzofuran-2- ylmethanol 331.8 331.2 decar- boxylates 0.1 357

2,3-Dihydro-1,4- benzodioxin-6-yl- methanol 350.0 349.2 decar-boxylates >0.03 358

(2-Phenyl-1,3- benzothiazol-5-yl)- methanol 469.0 468.2 <=10 359

(3-Ethyl-5,5,8,8- tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)methanol 430.1 429.3 decar- boxylates <=10

Example 350 2-Naphthylmethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.53-1.56 (3H), 2.20-2.22 (3H), 2.26-2.28 (3H),5.05-5.12 (1H), 5.40-5.45 (2H), 6.51-6.53 (1H), 6.85-6.96 (3H),7.18-7.21 (1H), 7.51-7.56 (3H), 7.80-7.81 (1H), 7.83-7.95 (3H)

Example 351 (4-Phenyl-2-furyl)methyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.48-1.56 (3H), 2.20-2.30 (6H), 4.42-4.51 (1H),4.80-4.86 (2H), 6.49-6.53 (2H), 6.85-7.01 (10H)h

Example 352 (6-Phenoxypyridin-3-yl)methyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.23-2.29 (6H), 5.01-5.10 (1H),5.20-5.30 (2H), 6.44-6.47 (1H), 6.84-6.88 (1H), 6.90-6.98 (3H),7.12-7.15 (2H), 7.20-7.24 (1H), 7.40-7.46 (2H), 7.50-7.51 (1H),7.65-7.67 (1H), 8.10-8.12 (1H)

Example 353 5-(6-Fluoro-1H-indol-1-yl)pentyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.22-1.28 (2H), 1.52-1.55 (3H), 1.60-1.66 (2H),1.80-1.85 (2H), 2.24-2.26 (3H), 2.35-2.37 (3H), 4.16-4.26 (4H),5.01-5.06 (1H), 6.40-6.42 (1H), 6.51-6.53 (1H), 6.80-6.90 (2H),6.96-6.99 (2H), 7.19-7.21 (1H), 7.22-7.23 (1H), 7.40-7.41 (1H),7.49-7.52 (1H)

Example 354 2-(6-Methoxy-1,5-naphthyridin-4-yl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.43-1.46 (3H), 2.21-2.26 (6H), 3.42-3.60 (2H),4.00-4.01 (3H), 4.61-4.75 (2H), 4.92-4.97 (1H), 6.51-6.53 (1H),6.82-6.95 (3H), 7.08-7.10 (1H), 7.29-7.30 (1H), 7.42-7.44 (1H),8.20-8.23 (1H), 8.61-8.63 (1H)

Example 355 2-(2-Naphthyl)ethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.55 (3H), 2.24-2.30 (6H), 3.10-3.15 (2H),4.45-4.60 (2H), 5.00-5.07 (1H), 6.52-6.55 (1H), 6.82-6.95 (3H),7.39-7.49 (4H), 7.71-7.72 (1H), 7.80-7.87 (3H)

Example 356 1-Benzofuran-2-ylmethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.52-1.56 (3H), 2.21-2.23 (3H), 2.30-2.32 (3H),5.03-5.10 (1H), 5.39-5.42 (2H), 6.45-6.47 (1H), 6.81-6.98 (4H),7.21-7.24 (1H), 7.30-7.34 (1H), 7.45-7.51 (2H), 7.62-7.64 (1H)

Example 357 2,3-Dihydro-1,4-benzodioxin-6-ylmethyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.24-2.29 (6H), 4.21-4.24 (4H),5.03-5.11 (3H), 6.50-6.53 (1H), 6.78-6.80 (2H), 6.82-6.88 (2H),6.96-6.99 (2H), 7.46-7.48 (1H)

Example 358 (2-Phenyl-1,3-benzothiazol-5-yl)methyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.51-1.54 (3H), 2.21-2.22 (3H), 2.27-2.28 (3H),5.02-5.09 (1H), 5.20-5.28 (2H), 6.50-6.52 (1H), 6.82-6.98 (3H),7.36-7.39 (1H), 7.58-7.61 (4H), 8.00-8.05 (2H), 8.14-8.18 (2H)

Example 359(3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate

¹H-NMR (d₆-Acetone): 1.09-1.15 (3H), 1.20-1.30 (12H), 1.50-1.54 (3H),1.64-1.66 (4H), 2.20-2.29 (6H), 2.50-2.60 (2H), 5.04-5.10 (1H),5.22-5.24 (2H), 6.52-6.55 (1H), 6.81-6.84 (1H), 6.92-6.95 (2H),7.20-7.21 (1H), 7.37-7.38 (1H), 7.44-7.45 (1H)

PREPARATIONS Preparation 1 2-[1-(2,3-Dimethylphenyl)vinyl]-1H-imidazole

The compound of Preparation 13 (80 mg, 0.37 mmol) was stirred at 50° C.in thionyl chloride (2 ml) for 1 h. The reaction was quenched into icedwater (5 ml) and then basified with dilute aqueous sodium hydroxidesolution. The aqueous phase was then extracted with dichloromethane(2×10 ml). The combined extracts were dried (MgSO₄) and concentrated invacuo to give the title compound (72 mg).

Alternative Synthesis

A solution of thionyl chloride (37 ml, 498 mmol) in acetonitrile (200ml) was added to the compound of Preparation 13 (48.90 g, 226 mmol). Theresulting solution was stirred at room temperature for 2 h, then pouredinto ice/water (600 ml), during which time the internal temperature wasmaintained at <25° C. The reaction mixture was then neutralised by theaddition of aqueous sodium hydroxide solution (4N) while maintaining thetemperature at <35° C. The mixture was adjusted to pH 6, and thesuspension obtained was filtered at room temperature. The light beigecrystalline solid obtained was washed with water (100 ml) and dried invacuo at 60° C. to give the title compound (30.6 g).

Experimental MH⁺ 199.2; expected 199.1

Alternative Synthesis

To a solution of the compound of Preparation 195 (1.0 kg, 3.25 mol) in2-propanol (10 L) was added palladium (10 wt. % on carbon, 100.0 g) andthe reaction mixture was heated at 60° C. under a hydrogen atmosphere(45-60 psi) for 24 h. The mixture was cooled and filtered through HiloSuper Cel®, washing through with 2-propanol (2×250 ml). The filtrate wasconcentrated in vacuo and diluted with acetonitrile (1300 ml) andstirred to get a solution. To this solution, was then added drop wiseeuphoric acid (conc., 1.2 L). The reaction mixture was stirred at 55° C.for 18 h. The mixture was cooled to −5° C., quenched with water (12.5l), and adjusted to pH 10 by addition of aqueous sodium hydroxidesolution (50%). The resulting solid was collected by filtration,reslurried with water (15.0 L) filtered, washed with water (2.5 L) anddried in vacuo at 50° C. to give the title compound (0.413 kg, purity byHPLC 99.80%).

Preparation 2 2-[1-(2,3-Difluorophenyl)vinyl]-1H-imidazole

A solution of the compound of Preparation 14 (240 mg, 1.1 mmol) andthionyl chloride (1.56 ml, 21.4 mmol) in acetonitrile (5 ml) was heatedat 70° C. for 10 h and then stirred at room temperature for 18 h. Themixture was concentrated in vacuo and to the residue was added toluene.This solution was concentrated in vacuo and the process was repeated.The residue was then partitioned between ethyl acetate (50 ml) andsaturated aqueous sodium hydrogen carbonate solution (30 ml). The twolayers were separated and the aqueous layer was extracted with ethylacetate (2×40 ml). The combined organic phases were dried (MgSO₄) andstirred with activated charcoal, before being filtered and concentratedin vacuo to give the title compound (325 mg).

Experimental MH⁺ 207.1; expected 207.1

Similarly prepared were:

MH⁺ Prep. Found/ From No Name Expected Prep. From 32-[1-(2-Chloro-6-fluoro-3- 237.1 88 1-(2-Chloro-6-fluoro-3-methyl-methylphenyl)vinyl]-1H-imidazole 237.1phenyl)-1-(1H-imidazol-2-yl)ethanol 4 2-[1-(4-Fluoro-3-methyl- 203.1 151-(4-Fluoro-3-methylphenyl)-1-(1H- phenyl)vinyl]-1H-imidazole 203.1imidazol-2-yl)ethanol 5 2-[1-(2,6-Difluorophenyl)vinyl]-1H- 207.3 161-(2,6-Difluorophenyl)-1-(1H- imidazole 207.1 imidazol-2-yl)ethanol 62-[1-(3-Fluoro-2-methyl- 203.3 17 1-(3-Fluoro-2-methylphenyl)-1-(1H-phenyl)vinyl]-1H-imidazole 203.1 imidazol-2-yl)ethanol 72-[1-(3-Fluorophenyl)vinyl]-1H- 189.3 181-(3-Fluorophenyl)-1-(1H-imidazol- imidazole 189.1 2-yl)ethanol 82-{1-[2-Chloro-3-(trifluoromethyl)- 273.1 211-[2-Chloro-3-(trifluoromethyl)- phenyl]vinyl}-1H-imidazole 273.0phenyl]-1-(1H-imidazol-2-yl)ethanol 9 2-[1-(3-Fluoro-5-methylphenyl)- —19 1-(3-Fluoro-5-methylphenyl)-1-(1H- vinyl]-1H-imidazoleimidazol-2-yl)ethanol 10 2-[1-(3,5-Difluorophenyl)vinyl]-1H- — 221-(3,5-Difluorophenyl)-1-(1H- imidazole imidazol-2-yl)ethanol 112-[1-(5-Methoxy-2,4- 229.3 20 1-(1H-Imidazol-2-yl)-1-(5-methoxy-dimethylphenyl)vinyl]-1H- 229.1 2,4-dimethylphenyl)ethanol imidazole 122-{1-[2-Fluoro-3-(trifluoromethyl)- 257.4 231-[2-Fluoro-3-(trifluoromethyl)- phenyl]vinyl}-1H-imidazole 257.1phenyl]-1-(1H-imidazol-2-yl)ethanol

Preparation 13 1-(2,3-Dimethylphenyl)-1-(1H-imidazol-2-yl)ethanol

1-(Diethoxymethyl)imidazole (76.0 g, 446 mmol) and N,N,N,N-tetramethylethylene diamine (67.6 mL, 446 mmol) were dissolved in2-methyltetrahydrofuran (400 ml) and cooled to −40° C., under nitrogen.n-Butyl lithium (2.5M in hexane, 180 ml, 446 mmol) was added slowlymaintaining the reaction temperature at <−25° C. throughout. Thereaction mixture was stirred for an hour and allowed to warm to 0° C.,after which 2,3-dimethylacetophenone (44.00 g, 297.00 mmol) was addedwhilst maintaining the reaction temperature at <15° C. throughout. Thereaction was stirred at room temperature overnight and then quenchedwith aqueous hydrochloric acid (2N, 1 l). The mixture was extracted withethyl acetate (500 ml) and to the aqueous layer was added sodiumcarbonate. The aqueous layer was further extracted with ethyl acetate(800 ml) and the combined extracts were washed with water (500 ml),dried (MgSO₄) and concentrated in vacuo to give the title compound (48.9g).

Experimental MH⁺ 217.2; expected 217.1

Alternative Synthesis

To a solution of methylmagnesium bromide (0.63 ml, 0.88 mmol) was addeda stirred solution of the compound of Preparation 24 (80 mg, 0.4 mmol)in anhydrous tetrahydrofuran at 0° C. The reaction mixture was stirredfor 30 min, quenched with saturated ammonium chloride solution, basifiedwith saturated sodium hydrogen carbonate solution and extracted withdichloromethane (2×3 ml). The organic layers were dried (MgSO₄) andconcentrated in vacuo to give the title compound (85 mg)

Experimental MH⁺ 217.2; expected 217.1

Preparation 14 1-(2,3-Difluorophenyl)-1-(1H-imidazol-2-yl)ethanol

To a solution of the compound of Preparation 25 (450 mg, 2.2 mmol) intetrahydrofuran (5 ml), at 0° C., was added methylmagnesium bromide (3Min diethyl ether, 2.16 ml, 6.5 mmol) and the reaction mixture wasstirred at room temperature for 1 h. To the mixture was addedhydrochloric acid (0.1M, 15 ml) and the mixture basified by addition ofsaturated aqueous sodium hydrogen carbonate solution. The mixture wasextracted with ethyl acetate (3×20 ml) and the combined organics weredried (MgSO₄) and concentrated in vacuo to give the title compound (240mg)

Experimental MH⁺ 225.1; expected 225.1

Similarly prepared were:

MH⁺ Prep. Found/ From No Name Expected Prep. From 151-(4-Fluoro-3-methylphenyl)-1-(1H- 221.1 26(4-Fluoro-3-methylphenyl)(1H- imidazol-2-yl)ethanol 221.1imidazol-2-yl)methanone 16 1-(2,6-Difluorophenyl)-1-(1H- — 27(2,6-Difluorophenyl)(1H- imidazol-2-yl)ethanol imidazol-2-yl)methanone17 1-(3-Fluoro-2-methylphenyl)-1-(1H- — 28 (3-Fluoro-2-methylphenyl)(1H-imidazol-2-yl)ethanol imidazol-2-yl)methanone 181-(3-Fluorophenyl)-1-(1H-imidazol- — 29 (3-Fluorophenyl)(1H-imidazol-2-2-yl)ethanol yl)methanone 19 1-(3-Fluoro-5-methylphenyl)-1-(1H- — 31(3-Fluoro-5-methylphenyl)(1H- imidazol-2-yl)ethanolimidazol-2-yl)methanone 20 1-(1H-Imidazol-2-yl)-1-(5-methoxy- 247.4 341H-Imidazol-2-yl(5-methoxy- 2,4-dimethylphenyl)ethanol 247.12,4-dimethylphenyl)methanone

Preparation 16

¹H-NMR (CD₃OD): 2.00-2.05 (3H), 6.84-6.95 (4H), 7.26-7.34 (1H)

Preparation 18

¹H-NMR (CD₃OD): 1.89-1.92 (3H), 6.89-6.96 (3H), 7.18-7.23 (2H),7.25-7.31 (1H)

Preparation 19

¹H-NMR (CDCl₃): 1.20-1.25 (3H), 2.21-2.27 (3H), 6.62-6.66 (1H),6.80-7.00 (3H), 7.41-7.49 (1H)

Preparation 211-[2-Chloro-3-(trifluoromethyl)phenyl]-1-(1H-imidazol-2-yl)ethanol

To a solution of the compound of Preparation 30 (1.1 g, 4.0 mmol) intetrahydrofuran (10 ml), at −78° C., was added drop wise methyllithium(1.6M in diethyl ether, 3 ml, 4.8 mmol). After stirring for 2 h, coldhydrochloric acid (0.1M) was added and the mixture was adjusted to pH 7by addition of potassium carbonate. The mixture was extracted with ethylacetate and the combined extracts were dried (MgSO₄) and concentrated invacuo to give the title compound (600 mg).

Similarly prepared were:

Prep. MH⁺ Found/ From No Name Expected Prep. From 221-(3,5-Difluorophenyl)-1-(1H- 225.4 32 (3,5-Difluorophenyl)(1H-imidazol-imidazol-2-yl)ethanol 225.1 2-yl)methanone 231-[2-Fluoro-3-(trifluoromethyl)- 275.5 33 [2-Fluoro-3-(trifluoromethyl)-phenyl]-1-(1H-imidazol-2- 275.1 phenyl](1H-imidazol-2-yl)- yl)ethanolmethanone

Preparation 24 (2,3-Dimethylphenyl)(1H-imidazol-2-yl)methanone

To the compound of Preparation 201 (200 mg, 1.0 mmol) in dichloromethane(10 ml) was added Dess Martin Periodinane (15% in dichloromethane, 3 ml)and the reaction mixture was stirred at room temperature for 30 min. Themixture filtered through silica, eluting with diethyl ether and thefiltrate was concentrated in vacuo. The residue was purified by flashchromatography (silica), with gradient elution, diethylether:dichloromethane [0:1 to 1:1]. The appropriate fractions werecombined and concentrated to give the title compound (100 mg).

Experimental MH⁺ 201.2; expected 201.1

Preparation 25 (2,3-difluorophenyl)(1H-imidazol-2-yl)methanone

To a solution of the compound of Preparation 37 (350 mg, 1.67 mmol) indichloromethane (20 ml) was added Dess-Martin Periodinane (780 mg, 1.80mmol) and the reaction mixture was stirred at room temperature for 1 h.The mixture was filtered through silica, washing through withdichloromethane and ethyl acetate and the filtrate was concentrated invacuo. To the residue as added ethyl acetate (100 ml) and the solutionwas washed with aqueous sodium metabisulphite solution (10%, 40 ml). Theaqueous phase was extracted with ethyl acetate (100 ml) and the combinedorganic phases were dried (MgSO₄) and concentrated in vacuo to give thetitle compound (450 mg)

Experimental MH⁺ 209.1; expected 209.1

Similarly prepared were:

MH⁺ Prep. Found/ From No Name Expected Prep. From 26(4-Fluoro-3-methylphenyl)(1H- 205.3 38 (4-Fluoro-3-methylphenyl)(1H-imidazol-2-yl)methanone 205.1 imidazol-2-yl)methanol 27(2,6-Difluorophenyl)(1H-imidazol-2- 209.1 39(2,6-Difluorophenyl)(1H-imidazol-2- yl)methanone 209.1 yl)methanol 28(3-Fluoro-2-methylphenyl)(1H- 205.3 40 (3-Fluoro-2-methylphenyl)(1H-imidazol-2-yl)methanone 205.1 imidazol-2-yl)methanol 29(3-Fluorophenyl)(1H-imidazol-2- 191.1 41 (3-Fluorophenyl)(1H-imidazol-2-yl)methanone 191.1 yl)methanol 30 [2-Chloro-3-(trifluoromethyl)- No data42 [2-Chloro-3-(trifluoromethyl)- phenyl](1H-imidazol-2-yl)methanonephenyl](1H-imidazol-2-yl)methanol 31 (3-Fluoro-5-methylphenyl)(1H- 205.343 (3-Fluoro-5-methylphenyl)(1H- imidazol-2-yl)methanone 205.1imidazol-2-yl)methanol 32 (3,5-Difluorophenyl)(1H-imidazol-2- 209.3 44(3,5-Difluorophenyl)(1H-imidazol-2- yl)methanone 209.1 yl)methanol 33[2-Fluoro-3-(trifluoromethyl)phenyl]- 259.4 46[2-Fluoro-3-(trifluoromethyl)phenyl]- (1H-imidazol-2-yl)methanone 259.1(1H-imidazol-2-yl)methanol

Preparation 34 1H-Imidazol-2-yl(5-methoxy-2,4-dimethylphenyl)methanone

To a solution of the compound of Preparation 45 (433 mg, 1.8 mmol) inethyl acetate (10 ml) was added manganese (IV) oxide (810 mg, 9.3 mmol)and the reaction mixture was stirred at room temperature for 3 h. Themixture was filtered through Arbocel®, washing through with ethylacetate, and the filtrate was concentrated in vacuo to give the titlecompound (440 mg).

Experimental MH⁺ 231.3; expected 231.1

Preparation 35 1-(2,3-Dimethylphenyl)propan-1-one

A mixture of the compound of Preparation 192 (1.0 g, 6.1 mmol) andDess-Martin Periodinane (2.58 g, 6.1 mmol) in dichloromethane (20 ml)was stirred at room temperature for 1 h. The mixture was then purifiedby column chromatography (silica), eluting withdichloromethane:cyclohexane [1:1]. The appropriate fractions werecombined and concentrated to give the title compound (0.95 g).

¹H-NMR (CDCl₃): 1.11-1.19 (3H), 2.23-2.29 (6H), 2.79-2.87 (2H),7.07-7.12 (1H), 7.17-7.27 (3H)

Preparation 36 (1-Benzyl-1H-imidazol-2-yl)(2,3-dimethylphenyl)methanone

A solution of 2,3-dimethylbenzoic acid (100 g, 666 mmol) in thionylchloride (350 ml) was heated at 80° C. for 1 h, before cooling to roomtemperature and concentrating in vacuo. To the residue was added toluene(100 ml) and the solution was again concentrated in vacuo. Theintermediate acid chloride was added to a mixture of 1-benzylimidazole(100 g, 632 mmol) and triethylamine (100 ml) in acetonitrile (1 l) andthe reaction mixture was heated at reflux for 18 h. The reaction mixturewas concentrated in vacuo and to the residue was added diethyl ether(500 ml) and ethyl acetate (50 ml). This solution was washed with water(500 ml) and saturated aqueous sodium hydrogen carbonate solution (500ml), filtered through silica gel (100 g) and concentrated in vacuo togive the title compound (182 g).

Experimental MH⁺ 291.4; expected 291.1

Alternative Synthesis

To a solution of 2,3-dimethylbenzoic acid (2.0 kg, 13.2 mol) in toluene(20 L) was added N,N-dimethylformamide (20 ml), followed by oxalylchloride (2.0 kg, 15.6 mol) at room temperature. The reaction mixturewas stirred at room temperature for 4 h and monitored by thin layerchromatography. If necessary, excess oxalyl chloride (25 g) was addeduntil no starting material was observed. Excess toluene and oxalylchloride were removed by distillation under vacuum at temperatures below70° C. To the residue was added toluene (150 ml) and the mixture wasagain concentrated in vacuo to give 2,3-dimethylbenzoyl chloride (2.0kg).

To a solution of 1-benzyl-1H-imidazole (1.69 Kg, 10.56 mol) indichloromethane (14.0 L), at −7° C., was added triethylamine (1.61 kg,10.56 mol). A solution of 2,3-dimethylbenzoyl chloride (2.0 kg, 11.99mol) in dichloromethane (6.0 L) was then added drop wise and thereaction mixture was stirred at room temperature for 16 h. The reactionwas monitored by Thin layer Chromatography. After completion of thereaction, the reaction mixture was diluted with water (5.0 L) and themixture was stirred for a further 15 min. The two layers were separatedand the organic phase was concentrated in vacuo. To the residue wasadded toluene (8.0 L) and the solution was cooled to −5° C., beforeaddition of hydrochloric acid (5N, 8.0 L). The two layers were separatedand the aqueous layer was adjusted to pH 9-12, by addition of aqueoussodium hydroxide solution (50%), and extracted with toluene (4.0 L andthen 8.0 L). The combined organic phases were concentrated in vacuo togive the title compound (2.8 kg).

Preparation 37 (2,3-Difluorophenyl)(1H-imidazol-2-yl)methanol

To a solution of 1-(diethoxymethyl)-1H-imidazole (1.65 ml, 10.1 mmol) intetrahydrofuran (15 ml), at −60° C. and under nitrogen, was addedn-butyllithium (2.5 M in hexanes, 4.03 ml, 10.1 mmol). The reactionmixture was stirred at −60° C. for 1 h, before addition of2,3-difluorobenzaldehyde (1.00 ml, 9.2 mmol), and then allowed to warmto room temperature over 18 h. The mixture was concentrated in vacuo andto the residue was added ethyl acetate (50 ml) and hydrochloric acid(3M, 50 ml). The two layers were separated and the aqueous phase wasbasified with aqueous sodium hydroxide solution (20%) and extracted withethyl acetate (3×100 ml). The combined organic phases were dried (MgSO₄)and concentrated in vacuo and the residue was re-crystallised from2-propanol to give the title compound (1.25 g)

Experimental MH⁺ 211.1; expected 211.1

Similarly prepared were:

Prep. MH+ Found/ No Name Expected From From 38(4-Fluoro-3-methylphenyl)(1H- 207.2 — 4-Fluoro-3-methyl-imidazol-2-yl)methanol 207.1 benzaldehyde 39(2,6-Difluorophenyl)(1H-imidazol-2- 211.1 — 2,6-Difluoro-benzaldehydeyl)methanol 211.1 40 (3-Fluoro-2-methylphenyl)(1H- 207.3 —3-Fluoro-2-methyl- imidazol-2-yl)methanol 207.1 benzaldehyde 41(3-Fluorophenyl)(1H-imidazol-2- 193.1 — 3-Fluoro-benzaldehydeyl)methanol 193.1 42 [2-Chloro-3-(trifluoromethyl)- — —2-Chloro-3-(trifluoromethyl)- phenyl](1H-imidazol-2-yl)methanolbenzaldehyde 43 (3-Fluoro-5-methylphenyl)(1H- 207.3 — 3-Fluoro-5-methyl-imidazol-2-yl)methanol 207.1 benzaldehyde 44(3,5-Difluorophenyl)(1H-imidazol-2- 211.3 — 3,5-Difluoro-benzaldehydeyl)methanol 211.1 45 1H-Imidazol-2-yl(5-methoxy-2,4- 233.3 Prep.5-Methoxy-2,4-dimethyl- dimethylphenyl)methanol 233.1 190 benzaldehyde46 [2-Fluoro-3-(trifluoromethyl)- 261.4 — 2-Fluoro-3-(trifluoromethyl)-phenyl](1H-imidazol-2-yl)methanol 261.1 benzaldehyde

Preparation 47 2-[1-(2,3-Dimethylphenyl)prop-1-en-1-yl]-1H-imidazole

A solution of the compound of Preparation 83 (350 mg, 1.52 mmol) inhydrochloric acid (2N, 50 ml) was heated at reflux for 18 h. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between dichloromethane (20 ml) and aqueous sodium hydrogencarbonate solution (20 ml). The two layers were separated and theaqueous phase was extracted with dichloromethane (2×20 ml). The combinedorganic phases were dried (MgSO₄) and concentrated in vacuo to give thetitle compound (255 mg).

Experimental MH⁺ 213.2; expected 213.1

Preparation 48 2-[1-(3-Methylphenyl)vinyl]-1H-imidazole

A solution of the compound of Preparation 78 (850 mg, 4.2 mmol) inhydrochloric acid (6N, 20 ml) was heated at reflux for 18 h. Thereaction mixture was concentrated in vacuo and the residue waspartitioned between dichloromethane (20 ml) and water (10 ml). Themixture was adjusted to pH 7 by addition of saturated aqueous sodiumhydrogen carbonate solution and the two layers were separated. Theorganic phase was dried (MgSO₄) and concentrated in vacuo to give thetitle compound (800 mg).

Experimental MH⁺ 185.3; expected 185.1

Similarly prepared were:

MH⁺ Prep. Found/ From No Name Expected Prep. From 492-[1-(2,5-Dimethylphenyl)vinyl]- 217.0 80 1-(2,5-Dimethylphenyl)-1-(1H-1H-imidazole 217.3 imidazol-2-yl)ethanol 502-[1-(3,5-Dimethylphenyl)vinyl]- 199.3 82 1-(3,5-Dimethylphenyl)-1-(1H-1H-imidazole 199.1 imidazol-2-yl)ethanol 51 2-{1-[2- 239.4 791-(1H-imidazol-2-yl)-1-[2- (Trifluoromethyl)phenyl]vinyl}- 239.1(trifluoromethyl)phenyl]ethanol 1H-imidazole 522-[1-(2,3-Dichlorophenyl)vinyl]- 239.2 84 1-(2,3-Dichlorophenyl)-1-(1H-1H-imidazole 239.0 imidazol-2-yl)ethanol 532-[1-(3,4-Dichlorophenyl)vinyl]- 239.2 85 1-(3,4-Dichlorophenyl)-1-(1H-1H-imidazole 239.0 imidazol-2-yl)ethanol 542-[1-(3-Chlorophenyl)vinyl]-1H- 205.1 861-(3-Chlorophenyl)-1-(1H-imidazol-2- imidazole 205.3 yl)ethanol 552-[1-(2,5-Dichlorophenyl)vinyl]- 239.2 87 1-(2,5-Dichlorophenyl)-1-(1H-1H-imidazole 239.0 imidazol-2-yl)ethanol 562-[1-(2,4-Dichlorophenyl)vinyl]- 239.2 98 1-(2,4-Dichlorophenyl)-1-(1H-1H-imidazole 239.0 imidazol-2-yl)ethanol 572-(1-Phenylvinyl)-1H-imidazole 171.2 991-(1H-Imidazol-2-yl)-1-phenylethanol 171.1 582-[1-(4-Methylphenyl)vinyl]-1H- 185.3 1001-(1H-Imidazol-2-yl)-1-(4-methyl- imidazole 185.1 phenyl)ethanol 592-(1-Mesitylvinyl)-1H-imidazole 213.4 1011-(1H-Imidazol-2-yl)-1-mesitylethanol 213.1 60 2-{1-[3- 239.3 1021-(1H-Imidazol-2-yl)-1-[3- (Trifluoromethyl)phenyl]vinyl}- 239.1(trifluoromethyl)phenyl]-ethanol 1H-imidazole 61 2-{1-[4- 239.3 1031-(1H-imidazol-2-yl)-1-[4- (Trifluoromethyl)phenyl]vinyl}- 239.1(trifluoromethyl)phenyl]-ethanol 1H-imidazole 62 2-[1-(3-Methoxy-2-215.3 104 1-(1H-Imidazol-2-yl)-1-(3-methoxy-2- methylphenyl)vinyl]-1H-215.1 methylphenyl)ethanol imidazole 63 2-[1-(2-Ethyl-3-methylphenyl)-213.3 105 1-(2-Ethyl-3-methylphenyl)-1-(1H- vinyl]-1H-imidazole 213.1imidazol-2-yl)ethanol 64 2-[1-(2-Bromo-3,5,6-trimethyl- 291.3 1061-(2-Bromo-3,5,6-trimethylphenyl)-1- phenyl)vinyl]-1H-imidazole 291.0(1H-imidazol-2-yl)ethanol 65 2-{1-[3- 255.1 1071-(1H-imidazol-2-yl)-1-[3- (Trifluoromethoxy)phenyl]vinyl}- 255.1(trifluoromethoxy)phenyl]ethanol 1H-imidazole 662-[1-(2,6-Dimethylphenyl)vinyl]- 199.3 109 1-(2,6-Dimethylphenyl)-1-(1H-1H-imidazole 199.1 imidazol-2-yl)ethanol

Preparation 67 2-[1-(2-Chloro-3-methylphenyl)vinyl]-1H-imidazole

A solution of the compound of Preparation 97 (1.22 g, 5.2 mmol) inEaton's Reagent (15 ml) was stirred at room temperature for 18 h. To themixture was added ethyl acetate and saturated aqueous sodium hydrogencarbonate solution and the two layers were separated. The organic phasewas washed with brine, dried (MgSO₄) and concentrated in vacuo to givethe title compound (1.00 g).

Experimental MH⁺ 219.3; expected 219.1

Similarly prepared were:

Prep. MH⁺ Found/ From No Name Expected Prep. From 682-[1-(3-Chloro-4-methylphenyl)- 219.3 93 1-(3-Chloro-4-methylphenyl)-1-vinyl]-1H-imidazole 219.1 (1H-imidazol-2-yl)ethanol 692-[1-(3-Chloro-2-methyl- 219.3 94 1-(3-Chloro-2-methylphenyl)-1-phenyl)vinyl]-1H-imidazole 219.1 (1H-imidazol-2-yl)ethanol 702-[1-(2-Chloro-5-methoxy- 235.3 95 1-(2-Chloro-5-methoxyphenyl)-1-phenyl)vinyl]-1H-imidazole 235.1 (1H-imidazol-2-yl)ethanol 712-[1-(2-Chloro-5-methyl- 219.3 96 1-(2-Chloro-5-methylphenyl)-1-phenyl)vinyl]-1H-imidazole 219.1 (1H-imidazol-2-yl)ethanol 722-{1-[3-Methyl-2-(trifluoromethyl)- 253.3 891-(1H-Imidazol-2-yl)-1-[3-methyl- phenyl]vinyl}-1H-imidazole 253.12-(trifluoromethyl)phenyl]ethanol 73 2-[1-(2,6-Difluoro-3-methyl- 221.3108 1-(2,6-Difluoro-3-methylphenyl)-1- phenyl)vinyl]-1H-imidazole 221.1(1H-imidazol-2-yl)ethanol 74 2-[1-(4-Chloro-3-methylphenyl)- 219.1 811-(4-Chloro-3-methylphenyl)-1- vinyl]-1H-imidazole 219.3(1H-imidazol-2-yl)ethanol

Preparation 75 2-[1-(2-Chloro-4-methoxyphenyl)vinyl]-1H-imidazole

A solution of the compound of Preparation 90 (703 mg, 2.7 mmol) intrifluoroacetic acid (15 ml) was heated at 50° C. for 18 h. The reactionmixture was concentrated in vacuo and the residue was neutralised byaddition of aqueous sodium hydrogen carbonate solution. The mixture wasextracted with ethyl acetate and the combined extracts were concentratedin vacuo to give the title compound (469 mg).

Experimental MH⁺ 235.3; expected 235.1

Similarly prepared were:

MH⁺ Prep. Found/ From No Name Expected Prep. From 76**2-[1-(3-Chloro-4-methoxy- 235.3 92 1-(3-Chloro-4-methoxyphenyl)-1-(1H-phenyl)vinyl]-1H-imidazole 235.1 imidazol-2-yl)ethanol 77**2-[1-(3-Chloro-2-methoxy- 235.3 91 1-(3-Chloro-2-methoxyphenyl)-1-(1H-phenyl)vinyl]-1H-imidazole 235.1 imidazol-2-yl)ethanol **The reaction toyield Preparation 76 gave some of Preparation 77 since Preparation 92contained some Preparation 91 and vice versa.

Preparation 78 1-(1H-Imidazol-2-yl)-1-(3-methylphenyl)ethanol

To a solution of 1-(diethoxymethyl)-1H-imidazole (935 mg, 5.5 mmol) inanhydrous tetrahydrofuran (6 ml), at −78° C., was added n-butyllithium(2.5M in hexanes, 2.2 ml, 5.5 mmol). The mixture was allowed to warm to0° C. and then added to a solution of 1-(3-methylphenyl)ethanone (670mg, 5.0 mmol) in anhydrous tetrahydrofuran (5 ml), also at 0° C. Thereaction mixture was stirred at 0° C. for 30 min and then at roomtemperature for 1 h. The mixture was poured into cold hydrochloric acid(4N, 10 ml) and stirred for 20 min. The mixture was adjusted to pH 7 byaddition of sodium hydrogen carbonate and then extracted withdichloromethane. The combined extracts were dried (MgSO₄) andconcentrated in vacuo to give the title compound (850 mg).

Experimental MH⁺ 203.3; expected 203.1

Similarly prepared were:

Prep. MH⁺ Found/ No Name Expected From From 791-(1H-Imidazol-2-yl)-1-[2- 257.3 — 1-[2-(Trifluoromethyl)phenyl]-(trifluoromethyl)phenyl]ethanol 257.1 ethanone 801-(2,5-Dimethylphenyl)-1-(1H- 217.3 — 1-(2,5-Dimethylphenyl)-imidazol-2-yl)ethanol 217.1 ethanone 81 1-(4-Chloro-3-methylphenyl)-1-237.3 — 1-(4-Chloro-3-methylphenyl)- (1H-imidazol-2-yl)ethanol 237.1ethanone 82 1-(3,5-Dimethylphenyl)-1-(1H- 217.3 Prep.1-(3,5-Dimethylphenyl)- imidazol-2-yl)ethanol 217.1 113 ethanone 831-(2,3-Dimethylphenyl)-1-(1H- 231.1 Prep. 351-(2,3-Dimethylphenyl)propan- imidazol-2-yl)propan-1-ol 231.1 1-one 841-(2,3-Dichlorophenyl)-1-(1H- 257.2 — 1-(2,3-Dichlorophenyl)ethanoneimidazol-2-yl)ethanol 257.0 85 1-(3,4-Dichlorophenyl)-1-(1H- 257.3 —1-(3,4-Dichlorophenyl)ethanone imidazol-2-yl)ethanol 257.0 861-(3-Chlorophenyl)-1-(1H- 3223.3 — 1-(3-Chlorophenyl)ethanoneimidazol-2-yl)ethanol 223.1 87 1-(2,5-Dichlorophenyl)-1-(1H- 257.2 —1-(2,5-Dichlorophenyl)ethanone imidazol-2-yl)ethanol 257.0 881-(2-Chloro-6-fluoro-3- 255.2 — 1-(2-Chloro-6-fluoro-3-methyl-methylphenyl)-1-(1H-imidazol- 255.1 phenyl)ethanone 2-yl)ethanol 891-(1H-Imidazol-2-yl)-1-[3- 271.4 Prep. 1-[3-Methyl-2-(trifluoromethyl)-methyl-2-(trifluoromethyl)- 271.1 170 phenyl]-ethanone phenyl]ethanol 901-(2-Chloro-4-methoxyphenyl)- 253.3 J. Org.1-(2-Chloro-4-methoxyphenyl)- 1-(1H-imidazol-2-yl)ethanol 253.1 Chem.,ethanone 2002, 67, 23, 8043  91* 1-(3-Chloro-2-methoxyphenyl)- 235.3Prep. 1-(3-Chloro-2-methoxyphenyl)- 1-(1H-imidazol-2-yl)ethanol 235.1173 ethanone  92* 1-(3-Chloro-4-methoxyphenyl)- 235.3 Prep.1-(3-Chloro-4-methoxy- 1-(1H-imidazol-2-yl)ethanol 235.1 174phenyl)ethanone 93 1-(3-Chloro-4-methylphenyl)-1- 237.3 Prep.1-(3-Chloro-4-methyl- (1H-imidazol-2-yl)ethanol 237.1 114phenyl)ethanone 94 1-(3-Chloro-2-methylphenyl)-1- 237.3 Prep.1-(3-Chloro-2-methylphenyl)- (1H-imidazol-2-yl)ethanol 237.1 111ethanone 95 1-(2-Chloro-5-methoxyphenyl)- 253.2 Prep.1-(2-Chloro-5-methoxy- 1-(1H-imidazol-2-yl)ethanol 253.1 175phenyl)ethanone 96 1-(2-Chloro-5-methylphenyl)-1- 237.3 Prep.1-(2-Chloro-5-methylphenyl)- (1H-imidazol-2-yl)ethanol 237.1 112ethanone 97 1-(2-Chloro-3-methylphenyl)-1- 237.3 Prep.1-(2-Chloro-3-methylphenyl)- (1H-imidazol-2-yl)ethanol 237.1 110ethanone 98 1-(2,4-Dichlorophenyl)-1-(1H- 257.2 —1-(2,4-Dichlorophenyl)ethanone imidazol-2-yl)ethanol 257.0 991-(1H-Imidazol-2-yl)-1-phenyl- 189.3 — 1-Phenylethanone ethanol 189.1100  1-(1H-Imidazol-2-yl)-1-(4- 203.3 — 1-(4-Methylphenyl)ethanonemethylphenyl)ethanol 203.1 101  1-(1H-Imidazol-2-yl)-1- 231.4 —1-Mesitylethanone mesitylethanol 231.1 102  1-(1H-Imidazol-2-yl)-1-[3-257.3 — 1-[3-(Trifluoromethyl)phenyl]- (trifluoromethyl)phenyl]ethanol257.1 ethanone 103  1-(1H-Imidazol-2-yl)-1-[4- 257.3 —1-[4-(Trifluoromethyl)phenyl]- (trifluoromethyl)phenyl]ethanol 257.1ethanone 104  1-(1H-Imidazol-2-yl)-1-(3- 233.3 Prep.1-(3-Methoxy-2-methyl- methoxy-2-methylphenyl)- 233.1 115phenyl)ethanone ethanol 105  1-(2-Ethyl-3-methylphenyl)-1- 231.3 Prep.1-(2-Ethyl-3-methylphenyl)- (1H-imidazol-2-yl)ethanol 231.1 178 ethanone106  1-(2-Bromo-3,5,6-trimethyl- — Prep. 1-(2-Bromo-3,5,6-trimethyl-phenyl)-1-(1H-imidazol-2- 180 phenyl)ethanone yl)ethanol 107 1-(1H-Imidazol-2-yl)-1-[3- — — 1-[3-(Trifluoromethoxy)-(trifluoromethoxy)phenyl]ethanol phenyl]ethanone 108 1-(2,6-Difluoro-3-methyl- 239.2 — 1-(2,6-Difluoro-3-methyl-phenyl)-1-(1H-imidazol-2- 239.1 phenyl)ethanone yl)ethanol 109 1-(2,6-Dimethylphenyl)-1-(1H- 216.4 — 1-(2,6-Dimethylphenyl)-imidazol-2-yl)ethanol 216.1 ethanone *The reaction to yield Preparation91 gave some of Preparation 92 since Preparation 173 contained somePreparation 174 and vice versa.

Preparation 107

¹H-NMR (CD₃OD): 1.89-1.94 (3H), 6.93-6.97 (2H), 7.08-7.13 (1H),7.33-7.41 (3H)

Preparation 110 1-(2-Chloro-3-methylphenyl)ethanone

To a solution of 2-chloro-3-methylbenzoic acid (1.71 g, 10.0 mmol) inanhydrous tetrahydrofuran (10 ml), at 0° C. and under nitrogen, wasadded methyllithium (1.6M in diethyl ether, 13.1 ml, 21.0 mmol), viasyringe. The reaction mixture was stirred at 0° C. for 30 min and thenallowed to warm to room temperature over 1 h. To the reaction mixturewas added cold hydrochloric acid (1M, 100 ml) and dichloromethane (110ml). The mixture was adjusted to pH 7 by addition of saturated aqueoussodium hydrogen carbonate solution and the two layers were separated.The aqueous layer was extracted with further dichloromethane and thecombined extracts were dried (MgSO₄) and concentrated in vacuo to givethe title compound (1.19 g).

¹H-NMR (CDCl₃): 2.37-2.39 (3H), 2.57-2.60 (3H), 7.15-7.20 (1H),7.23-7.31 (2H)

Similarly prepared were:

Prep. No. Name ¹H-NMR (CDCl₃) From 111 1-(3-Chloro-2-methylphenyl)-2.44-2.46 (3H), 2.52-2.54 (3H), 3-Chloro-2-methyl- ethanone 7.13-7.18(1H), 7.40-7.45 (1H) benzoic acid 112 1-(2-Chloro-5-methylphenyl)-1.67-1.69 (3H), 2.29-2.30 (3H), 2-Chloro-5- ethanone 7.13-7.18 (1H),7.22-7.25 (1H), methylbenzoic acid 7.30-7.32 (1H) 1131-(3,5-Dimethylphenyl)- 2.32-2.35 (6H), 2.53-2.55 (3H),3,5-Dimethylbenzoic ethanone 7.16-7.18 (1H), 7.52-7.54 (2H) acid 1141-(3-chloro-4-Methylphenyl)- 2.38-2.41 (3H), 2.53-2.55 (3H), 3-Chloro-4-ethanone 7.27-7.30 (1H), 7.69-7.72 (1H), methylbenzoic acid 7.88-7.90(1H)

Preparation 115 1-(3-Methoxy-2-methylphenyl)ethanone

A solution of 2-methyl-3-methoxybenzoic acid (10.0 g, 60.2 mmol) inthionyl chloride (50 ml) was heated at reflux for 1 h and then cooledand concentrated in vacuo. To the residue was added tetrahydrofuran (100ml) and iron (III) acetylacetonate (638 mg, 1.8 mmol) and the solutionwas cooled to −20° C., before addition of methylmagnesium bromide (3M indiethyl ether, 22.1 ml, 66.2 mmol). After stirring for 15 min, themixture was poured into saturated aqueous ammonium chloride solution andextracted with dichloromethane. The combined extracts were washed withsaturated aqueous sodium hydrogen carbonate solution, dried (MgSO₄) andconcentrated in vacuo.

The residue was purified by flash chromatography (silica), eluting withpentane:dichloromethane [1:1]. The appropriate fractions were combinedand concentrated to give the title compound (7.60 g).

¹H-NMR (CDCl₃): 2.27-2.29 (3H), 2.50-2.53 (3H), 3.79-3.83 (3H),6.90-6.94 (1H), 7.10-7.14 (1H), 7.16-7.21 (1H)

Preparation 116 Chloromethyl 3-cyclopentylpropanoate

Cyclopentylpropionyl chloride (2.0 g, 12.4 mmol) was added to a mixtureof paraformaldehyde (377 mg, 13.0 mmol) and zinc chloride at roomtemperature under nitrogen. The reaction mixture was heated to 75° C.for 3 hours, cooled and the mixture distilled (90°-100° C.) to give thetitle compound (1.10 g)

¹H-NMR (CDCl₃): 1.00-1.10 (2H), 1.45-1.75 (9H), 2.35-2.40 (2H),5.70-5.75 (2H)

Similarly prepared were:

Prep. No Name ¹H-NMR (CDCl₃): From 117 Chloromethyl 0.90-0.95 (3H),Heptanoyl heptanoate 1.20-1.40 (6H), chloride 1.60-1.70 (2H), 2.30-2.40(2H, 5.70-5.75 (2H) 118 Chloromethyl 3,3- — 3,3-Dimethylbutanoyldimethylbutanoate chloride

Preparation 119 Chloromethyl Cyclopropylmethyl Carbonate

To a solution of cyclopropylmethanol (0.39 ml, 5.0 mmol) and pyridine(0.40 ml, 5.0 mmol) in dichloromethane (4 ml), at 0° C. and undernitrogen, was added drop wise chloromethyl chlorocarbonate (0.40 ml, 4.5mmol). The reaction mixture was stirred at 0° C. for 30 min and then atroom temperature for 2 h. To the mixture was added diethyl ether (15 ml)and the solid material was collected by filtration and washed withdiethyl ether (10 ml). The combined organic phases were dried (MgSO₄)and concentrated in vacuo to give the title compound (725 mg) which wasused directly.

Similarly prepared were:

Prep. MH⁺ Found/ No Name Expected From 120 Chloromethyl 4- 345.4(4-Methoxy- methoxybenzyl carbonate 345.4 phenyl)methanol 121Chloromethyl 3-methylbutyl — 3-Methylbutan-1- carbonate ol 122Chloromethyl isopropyl — Propan-2-ol carbonate 123 Chloromethylcyclobutyl — Cyclobutanol carbonate 124 Chloromethyl 2,2,2- — 2,2,2-trifluoroethyl carbonate Trifluoroethanol

Preparation 125 Chloromethyl (2,4-Dichlorobenzyl)carbamate

To a solution of the compound of 1-(2,4-dichlorophenyl)methanamine (0.15ml, 1.1 mmol) in anhydrous dichloromethane (2 ml), at −10° C. and undernitrogen, was added drop wise 3-chloropropanoyl chloride (0.12 ml, 1.1mmol). The reaction mixture was allowed to warm to room temperature andstirred for 18 h. To the mixture was added dichloromethane (5 ml) andwater (5 ml) and the two layers were separated. The aqueous layer wasextracted with dichloromethane (10 ml) and the combined organic layerswere dried (MgSO₄) and concentrated in vacuo to give the title compound(285 mg).

¹H-NMR (CDCl₃): 4.35-4.39 (2H), 5.76-5.79 (2H), 7.11-7.15 (1H),7.37-7.44 (2H)

Similarly prepared were:

Prep. No Name ¹H-NMR (CDCl₃): From 126 Chloromethyl 2.99-3.14 (4H),3.98-4.08 (4H), Thiomorpholine 1,1-dioxide thiomorpholine-4- 5.78-5.81(2H) carboxylate 1,1-dioxide 127 1-(Chloromethyl) 2-methyl 1.90-2.00(3H), 2.20-2.30 (2H), Methyl L-prolinate (2S)-pyrrolidine-1,2- 3.45-3.55(2H), 3.76-3.79 (3H), hydrochloride dicarboxylate 4.35-4.42 (2H),5.70-5.73 (2H) 128 Chloromethyl cyclohexyl- 1.04-1.16 (4H), 1.23-1.35(3H), Cyclohexanamine carbamate 1.83-1.93 (3H), 3.42-3.52 (1H),5.66-5.69 (2H) 129 Chloromethyl [2-(2,4- 2.93-3.00 (2H), 3.45-3.51 (2H),2-(2,4-Dichlorophenyl)- dichlorophenyl)ethyl]- 5.72-5.75 (2H), 7.13-7.22(2H), ethanamine carbamate 7.36-7.41 (1H) 130 Chloromethyl cyclohexyl-1.00-1.13 (1H), 1.26-1.48 (4H), N-Methylcyclohexan-amine(methyl)-carbamate 1.62-1.86 (5H), 2.76-2.88 (3H), 3.77-4.04 (1H),5.76-5.84 (2H) 131 Chloromethyl benzyl- 2.86-2.94 (3H), 4.48-4.54 (2H),N-Methyl-1-phenyl- (methyl)-carbamate 5.83-5.85 (2H), 7.19-7.39 (5H)methanamine 132 Chloromethyl methyl(2- 1.50-1.67 (5H), 2.61-2.71 (2H),N-Methyl-2- phenylethyl)carbamate 5.75-5.90 (2H), 7.23-7.40 (5H)phenylethanamine

Preparation 133 1-Chloroethyl [2-(methylsulfonyl)ethyl]carbamate

To a solution of 2-(methylsulfonyl)ethanamine (176 mg, 1.1 mmol) and N,N-diisopropylethylamine (0.38 ml, 2.2 mmol) in anhydrous dichloromethane(2 ml), at 0° C., was added drop wise 3-chloropropanoyl chloride (0.12ml, 1.1 mmol). The reaction mixture was allowed to warm to roomtemperature and stirred for 62 h. To the mixture was added water (5 ml)and the two layers were separated. The aqueous layer was extracted withdichloromethane (2×5 ml) and the combined organic layers were dried(MgSO₄) and concentrated in vacuo to give the title compound (260 mg).

Similarly prepared were:

Prep. No Name From 134 1-Chloroethyl morpholine-4- Morpholinecarboxylate 135 1-(1-Chloroethyl) 2-methyl 2-methyl (2S)-pyrrolidine-(2S)-pyrrolidine-1,2- dicarboxylate 2-carboxylate

Preparation 1361-Benzyl-2-[1-(3-cyclopropyl-2-methylphenyl)vinyl]-1H-imidazole

To a solution of the compound of Preparation 140 (1.04 g, 3.0 mmol) intoluene (30 ml) was added potassium phosphate (1.88 g, 8.9 mmol) andcyclopropyl boronic acid (304 mg, 3.5 mmol). The mixture was de-gassedand tricyclohexylphosphine (83 mg, 0.3 mmol) was added. The mixture wasde-gassed again, before addition of palladium (II) acetate (33 mg). Thereaction mixture was then heated at reflux for 18 h. The mixture waspoured into ethyl acetate and water and the two layers were separated.The organic phase was washed with brine, dried (MgSO₄) and concentratedin vacuo. The residue was filtered through silica, eluting with ethylacetate:cyclohexane [1:1] and the filtrate was concentrated in vacuo togive the title compound (720 mg).

¹H-NMR (d₆-DMSO): 0.44-0.47 (2H), 0.80-0.83 (2H), 1.20-1.25 (1H),1.70-1.80 (2H), 1.89-1.91 (3H) 5.22-5.24 (1H), 5.61-5.63 (1H), 6.80-6.84(2H), 6.84-6.86 (1H), 6.86-6.89 (2H), 7.00-7.02 (1H), 7.17-7.23 (3H),7.40-7.45 (1H)

Similarly prepared were:

MH⁺ Prep. Found/ No Name Expected From Prep. From 1371-Benzyl-2-(1-biphenyl-3-yl- 337.2 147 and phenyl1-Benzyl-2-[1-(3-bromo- vinyl)-1H-imidazole 337.2 boronic acidphenyl)vinyl]-1H-imidazole 138 1-Benzyl-2-[1-(3-cyclopropyl- 301.3 1471-Benzyl-2-[1-(3-bromo- phenyl)vinyl]-1H-imidazole 301.2phenyl)vinyl]-1H-imidazole

Preparation 139 1-Benzyl-2-[1-(2-bromo-3-methylphenyl)vinyl]-1H-imidazole

To a suspension of the compound of Preparation 149 (3.1 g, 8.3 mmol) inacetonitrile (30 ml) was added thionyl chloride (12.2 ml, 167 mmol) andthe reaction mixture was heated at 60° C., under nitrogen, for 11 h. Themixture was concentrated in vacuo and to the residue was addedacetonitrile. This solution was concentrated in vacuo and the processwas repeated. To the final residue was added 2-propanol (40 ml) andactivated charcoal and the mixture was heated at 60° C. for 1 h. Themixture was concentrated in vacuo to give the title compound (3.1 g).

Experimental MH⁺ 353.3; expected 353.1

Similarly prepared were:

MH⁺ Prep. Found/ From No Name Expected Prep. From 1401-Benzyl-2-[1-(3-bromo-2- 353.0 151 1-(1-Benzyl-1H-imidazol-2-yl)-1-(3-methylphenyl)vinyl]-1H-imidazole 353.1 bromo-2-methylphenyl)ethanol 1411-Benzyl-2-{1-[3-bromo-2- 389.4 152 1-(1-Benzyl-1H-imidazol-2-yl)-1-[3-(difluoromethyl)phenyl]vinyl}-1H- 389.1 bromo-2-(difluoromethyl)-imidazole phenyl]ethanol 142 1-Benzyl-2-{1-[3-(difluoromethyl)- 311.2153 1-(1-Benzyl-1H-imidazol-2-yl)-1-[3- phenyl]vinyl}-1H-imidazole 311.1(difluoromethyl)phenyl]ethanol 143 1-Benzyl-2-[1-(2-fluoro-3- 293.3 1541-(1-Benzyl-1H-imidazol-2-yl)-1-(2- methylphenyl)vinyl]-1H-imidazole293.1 fluoro-3-methylphenyl)ethanol 144 1-Benzyl-2-{1-[2-methyl-5- — 1551-(1-Benzyl-1H-imidazol-2-yl)-1-[2- (trifluoromethyl)phenyl]vinyl}-1H-methyl-5-(trifluoromethyl)phenyl]- imidazole ethanol 1451-Benzyl-2-[1-(3-bromo-5- — 156 1-(1-Benzyl-1H-imidazol-2-yl)-1-(3-methylphenyl)vinyl]-1H-imidazole bromo-5-methylphenyl)ethanol 1461-Benzyl-2-[1-(3-ethylphenyl)- 289.2 1771-(1-Benzyl-1H-imidazol-2-yl)-1-(3- vinyl]-1H-imidazole 289.2ethylphenyl)ethanol 147 1-Benzyl-2-[1-(3-bromo- 339.0 1501-(1-Benzyl-1H-imidazol-2-yl)-1-(3- phenyl)vinyl]-1H-imidazole 339.0bromophenyl)ethanol

Preparation 145

¹H-NMR (CDCl₃): 2.20-2.25 (3H), 4.80-4.84 (2H), 5.66-5.70 (1H),5.81-5.84 (1H), 6.88-6.95 (4H), 7.10-7.14 (1H), 7.21-7.29 (5H)

Preparation 1481-Benzyl-2-{1-[2-methyl-3-(trifluoromethyl)phenyl]vinyl}-1H-imidazole

A solution of the compound of Preparation 157 (4.90 g, 13.6 mmol) inEaton's Reagent (50 ml) was stirred at room temperature for 40 h. Themixture was poured into ice/water (200 ml) and adjusted to pH 7 byaddition of saturated aqueous sodium hydrogen carbonate solution. Themixture was extracted with ethyl acetate (2×100 ml) and the combinedextracts were dried (MgSO₄) and concentrated in vacuo to give the titlecompound (3.1 g).

Experimental MH⁺ 343.3; expected 343.1

Preparation 1491-(1-Benzyl-1H-imidazol-2-yl)-1-(2-bromo-3-methylphenyl)ethanol

To a solution of the compound of Preparation 158 (3.38 g, 9.5 mmol) intetrahydrofuran (30 ml), at 0° C. and under nitrogen, was added dropwise methylmagnesium bromide (3M, 6.34 ml, 19 mmol). The reactionmixture was allowed to warm to room temperature and stirred for 18 h. Tothe mixture was added hydrochloric acid (0.1M, 25 ml), and the solutionwas basified by addition of saturated aqueous sodium hydrogen carbonatesolution, and the mixture was extracted with ethyl acetate (4×30 ml).The combined extracts were washed with brine (20 ml), dried (MgSO₄) andconcentrated in vacuo to give the title compound (3.10 g).

Experimental MH⁺ 371.3; expected 371.1

Similarly prepared were:

MH⁺ Prep. Found/ From No Name Expected Prep. From 1501-(1-Benzyl-1H-imidazol-2-yl)-1- — 159 (1-Benzyl-1H-imidazol-2-yl)(3-(3-bromophenyl)ethanol bromophenyl)methanone 1511-(1-Benzyl-1H-imidazol-2-yl)-1- 371.2 160(1-Benzyl-1H-imidazol-2-yl)(3- (3-bromo-2-methylphenyl)ethanol 371.1bromo-2-methylphenyl)methanone 152 1-(1-Benzyl-1H-imidazol-2-yl)-1-407.4 161 (1-Benzyl-1H-imidazol-2-yl)[3- [3-bromo-2-(difluoromethyl)-407.1 bromo-2-(difluoromethyl)phenyl]- phenyl]ethanol methanone 1531-(1-Benzyl-1H-imidazol-2-yl)-1- 329.3 162(1-Benzyl-1H-imidazol-2-yl)[3- [3-(difluoromethyl)phenyl]ethanol 329.1(difluoromethyl)phenyl]-methanone 154 1-(1-Benzyl-1H-imidazol-2-yl)-1-311.5 163 (1-Benzyl-1H-imidazol-2-yl)(2-(2-fluoro-3-methylphenyl)ethanol 311.2 fluoro-3-methylphenyl)methanone155 1-(1-Benzyl-1H-imidazol-2-yl)-1- 361.0 164(1-Benzyl-1H-imidazol-2-yl)[2- [2-methyl-5-(trifluoromethyl)- 361.2methyl-5-(trifluoromethyl)phenyl]- phenyl]ethanol methanone 1561-(1-Benzyl-1H-imidazol-2-yl)-1- — 165 (1-Benzyl-1H-imidazol-2-yl)(3-(3-bromo-5-methylphenyl)ethanol bromo-5-methylphenyl)methanone 1571-(1-Benzyl-1H-imidazol-2-yl)-1- 361.3 166(1-Benzyl-1H-imidazol-2-yl)[2- [2-methyl-3-(trifluoromethyl)- 361.2methyl-3-(trifluoromethyl)phenyl]- phenyl]ethanol methanone

Preparation 156

¹H-NMR (CDCl₃): 2.07-2.15 (3H), 2.42-2.48 (3H), 4.93-5.00 (2H),6.75-6.93 (5H), 7.05-7.16 (5H)

Preparation 158 (1-Benzyl-1H-imidazol-2-yl)(2-bromo-3-methylphenyl)methanone

A solution of 2-bromo-3-methylbenzoic acid (2.0 g, 9.3 mmol) in thionylchloride (4.75 ml, 65.1 mmol) was heated at 65° C., under nitrogen, for3 h. The mixture was concentrated in vacuo and to the residue was addedacetonitrile (25 ml). This solution was concentrated in vacuo and theprocess was repeated. To the final residue was added acetonitrile (25ml), 1-benzylimidazole (1.62 g, 10.2 mmol) and triethylamine (1.44 ml,10.2 mmol) and the reaction mixture was heated at 60° C., undernitrogen, for 18 h. The mixture was concentrated in vacuo and to theresidue was added ethyl acetate (80 ml). The solution was washed withwater (40 ml) and saturated aqueous sodium hydrogen carbonate solution(40 ml), dried (MgSO₄) and concentrated in vacuo to give the titlecompound (3.38 g).

Similarly prepared were:

MH⁺ Prep. Found/ From No Name Expected Prep. From 159(1-Benzyl-1H-imidazol-2-yl)(3- 341.1 — 3-Bromobenzoic acidbromophenyl)methanone 341.0 160 (1-Benzyl-1H-imidazol-2-yl)(3-bromo-355.1 — 3-Bromo-2-methylbenzoic acid 2-methylphenyl)-methanone 355.0 161(1-Benzyl-1H-imidazol-2-yl)[3-bromo- 391.2 1823-Bromo-2-(difluoromethyl)- 2-(difluoromethyl)-phenyl]methanone 391.0benzoic acid 162 (1-Benzyl-1H-imidazol-2-yl)[3- — 1873-(Difluoromethyl)benzoic acid (difluoromethyl)phenyl]-methanone 163(1-Benzyl-1H-imidazol-2-yl)(2-fluoro- 295.3 — 2-Fluoro-3-methylbenzoicacid 3-methylphenyl)methanone 295.1 164(1-Benzyl-1H-imidazol-2-yl)[2-methyl- 345.3 —2-Methyl-5-(trifluoromethyl)- 5-(trifluoromethyl)phenyl]-methanone 345.1benzoic acid 165 (1-Benzyl-1H-imidazol-2-yl)(3-bromo- — 1883-Bromo-5-methylbenzoic acid 5-methylphenyl)methanone 166(1-Benzyl-1H-imidazol-2-yl)[2-methyl- 345.2 —2-Methyl-3-(trifluoromethyl)- 3-(trifluoromethyl)-phenyl]methanone 345.1benzoic acid

Preparation 162

¹H-NMR (CDCl₃): 5.69-5.71 (2H), 6.81-6.85 (1H), 7.17-7.20 (2H),7.21-7.24 (2H), 7.30-7.40 (3H), 7.71-7.73 (1H), 8.39-8.42 (2H)

Preparation 165

¹H-NMR (CDCl₃): 2.35-2.38 (3H), 5.61-5.65 (2H), 7.15-7.37 (8H),7.46-7.50 (1H), 7.92-7.97 (1H)

Preparation 1672-[1-(1-benzyl-1H-imidazol-2-yl)vinyl]-6-methylbenzonitrile

A mixture of the compound of Preparation 139 (150 mg, 0.43 mmol),potassium hexacyanoferrate(II) (dried in vacuo at 85° C., 36 mg, 0.08mmol), copper(I) iodide (8 mg), potassium iodide (7 mg),1-methyl-2-pyrrolidinone (2 ml) and dimethylethylenediamine (49 μl) wasplaced in a pressure tube and degassed with nitrogen (×3). The tube wassealed and heated at 140° C. for 100 h. To the mixture was added ethylacetate (10 ml) and water (10 ml) and the two layers were separated. Theorganic phase was dried (MgSO₄) and concentrated in vacuo to give thetitle compound (160 mg)

Experimental MH⁺ 300.3; expected 300.2

Preparation 1683-[1-(1-Benzyl-1H-imidazol-2-yl)vinyl]-2-methylbenzonitrile

To a solution of the compound of Preparation 140 (100 mg, 0.28 mmol) in1-methyl-2-pyrrolidinone (3 ml) was added sodium cyanide (28 mg, 0.57mmol) and nickel (II) bromide (62 mg, 0.28 mmol). The reaction mixturewas sealed and heated in a microwave (150 W) at 150° C. for 5 min. Tothe mixture was added water (10 ml) and the solution was extracted withdiethyl ether (4×10 ml). The combined extracts were washed with water(10 ml) and brine (10 ml), dried (MgSO₄) and concentrated in vacuo. Tothe residue was added 2-propanol (15 ml) and activated charcoal and thesolution was heated at 60° C. for 1 h. The mixture was then filteredthrough Arbocel® and the filtrate was concentrated in vacuo to give thetitle compound (40 mg).

Experimental MH⁺ 300.4; expected 300.2

Preparation 1693-[1-(1-Benzyl-1H-imidazol-2-yl)vinyl]-5-methylbenzonitrile

To a solution of the compound of Preparation 145 (1.1 g, 3.1 mmol) inN,N -dimethylacetamide (30 ml) was added copper (I) cyanide (641 mg, 7.1mmol) and the reaction mixture was heated at 150° C. for 3 days. Thereaction mixture was poured into ethyl acetate and the mixture waswashed with water and brine. The aqueous phase was filtered and thesolid material was collected by filtration and dissolved in ethylacetate, water and N,N,N′-tetramethylethylenediamine. The two layerswere separated and the organic phase was washed with brine, dried(MgSO₄) and concentrated in vacuo. The residue was filtered throughcharcoal and silica, eluting with ethyl acetate and the filtrate wasconcentrated in vacuo to give the title compound (210 mg).

¹H-NMR (CDCl₃): 2.24-2.28 (3H), 4.80-4.92 (2H), 5.56-5.60 (1H),5.78-5.82 (1H), 6.88-6.97 (3H), 7.10-7.14 (1H), 7.19-7.33 (6H)

Preparation 170 1-[3-Methyl-2-(trifluoromethyl)phenyl]ethanone

To a solution of the compound of Preparation 171 (427 mg, 2.1 mmol) indichloromethane (20 ml) was added Dess-Martin periodinane (25%, 3.83 ml,2.3 mmol) and the reaction mixture was stirred at room temperature for18 h. The reaction mixture was filtered through silica, eluting withdichloromethane, followed by diethyl ether. The filtrate was washed withsaturated aqueous sodium hydrogen carbonate solution, dried (MgSO₄) andconcentrated in vacuo. To the residue was added dichloromethane and thesolution was filtered through silica. The filtrate was dried (MgSO₄) andconcentrated in vacuo. The residue was dissolved in tetrahydrofuran andre-concentrated to give the title compound (332 mg).

¹H-NMR (CDCl₃): 1.80-1.85 (3H), 3.75-3.79 (3H), 7.04-7.07 (1H),7.31-7.33 (1H), 7.40-7.43 (1H)

Preparation 171 1-[3-Methyl-2-(trifluoromethyl)phenyl]ethanol

To a solution of the compound of Preparation 172 (500 mg, 2.1 mmol) intetrahydrofuran (22 ml), at −78° C., was added n-butyllithium (2.5M inhexanes, 0.92 ml, 2.3 mmol). After stirring for 45 min, acetaldehyde(0.14 ml, 2.5 mmol) was added and the reaction mixture was allowed towarm to room temperature over 18 h. To the mixture was added saturatedaqueous ammonium chloride solution and the mixture was extracted withethyl acetate. The combined extracts were washed with brine, dried(MgSO₄) and concentrated in vacuo to give the title compound (600 mg).

¹H-NMR (CDCl₃): 1.42-1.45 (3H), 2.49-2.53 (3H), 5.38-5.42 (1H),7.16-7.19 (1H), 7.40-7.43 (1H), 7.65-7.68 (1H)

Preparation 172 1-Bromo-3-methyl-2-(trifluoromethyl)benzene

A mixture of 2-bromo-6-methylbenzoic acid (10.0 g, 47.0 mmol) andsulphur tetrafluoride (5.02 g, 46.5 mmol) was heated in hydrofluoricacid (930 mg, 46.5 mmol) at 110° C. To the reaction mixture was addedethyl acetate and water and the two layers were separated. The organicphase was dried (MgSO₄) and concentrated in vacuo. The residue wasdistilled under reduced pressure (bp 30-33° C. at 1 mmHg) to give thetitle compound (1.83 g).

Preparation 173 1-(3-Chloro-2-methoxyphenyl)ethanone

To the compound of Preparation 193 (697 mg, 4.1 mmol) in acetone (30 ml)was added potassium carbonate (1.13 g, 8.2 mmol), followed by methyliodide (2.0 ml, 4.66 g, 32.8 mmol). The reaction mixture was heated at40° C. for 18 h, cooled and concentrated in vacuo. The residue waspartitioned between ethyl acetate and water and the organic phase wasseparated, washed with brine, dried (MgSO₄) and concentrated in vacuo togive the title compound (450 mg) as a mixture of regioisomers.

¹H-NMR (CDCl₃): 2.58-2.62 (3H), 3.92-3.95 (3H), 7.47-7.51 (1H),7.82-7.86 (1H), 7.94-7.97 (1H)

Similarly prepared was:

Prep. From No Name Prep. From 174*** 1-(3-chloro-4-methoxyphenyl)- 1931-(3-chloro-4-hydroxy- ethanone phenyl)ethanone ***The reaction to yieldPreparation 174 gave some of Preparation 173 since Preparation 193contained a mixture of 1-(3-chloro-2-hydroxyphenyl)ethanone and1-(3-chloro-4-hydroxyphenyl)ethanone

Preparation 174

¹H-NMR (CDCl₃): 2.58-2.62 (3H), 3.92-3.95 (3H), 7.47-7.51 (1H),7.82-7.86 (1H), 7.94-7.97 (1H)

Preparation 175 1-(2-Chloro-5-methoxyphenyl)ethanone

To a solution of SELECTFLUOR™ (5.0 g, 14.1 mmol) and sodium chloride(825 mg, 14.1 mmol) in acetonitrile (200 ml), under nitrogen, was added1-(3-methoxyphenyl)ethanone (1.94 ml, 14.1 mmol) and the reactionmixture was stirred at room temperature for 5 days. To the mixture wasadded distilled water (200 ml) and the solution was extracted withdichloromethane (2×100 ml). The combined extracts were dried (MgSO₄) andconcentrated in vacuo. The residue was purified by column chromatography(silica) with gradient elution, ethyl acetate:cyclohexane [5:95 to10:90]. The appropriate fractions were combined and concentrated to givethe title compound (1.12 g).

¹H-NMR (CDCl₃): 2.59-2.65 (3H), 3.76-3.80 (3H), 6.88-6.91 (1H),7.01-7.04 (1H), 7.25-7.28 (1H)

Preparation 176 1-Benzyl-2-[1-(3-ethyl-2-methylphenyl)vinyl]-1H-imidazole

To a solution of the compound of Preparation 140 (207 mg, 0.3 mmol) inN,N-dimethylformamide (28 ml) was added potassium carbonate (1.17 g, 8.5mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride(550 mg) and triethylborane (1M, 6.79 ml, 6.8 mmol). The reactionmixture was heated at reflux for 60 h, cooled and concentrated in vacuo.To the residue was added ethyl acetate and water and the two layers wereseparated. The organic phase was washed with water and brine, dried(MgSO₄) and concentrated in vacuo to give the title compound (110 mg).

Experimental MH⁺ 303.2; expected 303.2

Preparation 177 1-(1-Benzyl-1H-imidazol-2-yl)-1-(3-ethylphenyl)ethanol

To a solution of the compound of Preparation 150 (500 mg, 1.4 mmol) inN,N -dimethylformamide (14 ml) was added potassium carbonate (193 mg,1.4 mmol) and triethylborane (1M, 3.36 ml, 3.4 mmol). The mixture wasde-oxygenated and [1,1′-bis(diphenylphosphino)ferrocene]palladium (II)chloride (114 mg) was added. The reaction mixture was heated at 50° C.for 18 h, cooled and concentrated in vacuo. To the residue was addedethyl acetate and water and the two layers were separated. The organicphase was washed with water and brine, dried (MgSO₄) and concentrated invacuo to give the title compound (500 mg).

Experimental MH⁺ 307.3; expected 307.2

Preparation 178 1-(2-Ethyl-3-methylphenyl)ethanone

To a solution of the compound of Preparation 179 (367 mg, 1.7 mmol) inanhydrous N,N-dimethylformamide (10 ml), under nitrogen, was addedpotassium carbonate (4.52 g, 32.7 mmol), followed by[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (141 mg)and triethylborane (1M in tetrahydrofuran, 4.13 ml, 4.13 mmol). Thereaction mixture was heated at 50° C. for 18 h, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(Biotage™ 40M cartridge), eluting with ethyl acetate:pentane [5:95]. Theappropriate fractions were combined and concentrated to give the titlecompound (160 mg).

¹H-NMR (CDCl₃): 1.15-1.20 (3H), 2.35-2.38 (3H), 2.55-2.58 (3H),2.74-2.81 (2H), 7.12-7.17 (1H), 7.23-7.27 (1H), 7.36-7.40 (1H)

Preparation 179 1-(2-Bromo-3-methylphenyl)ethanone

To a solution of 1-(2-amino-3-methylphenyl)ethanone (Helv. Chim. Acta;EN; 62, 1979, 271-303) (850 mg, 5.7 mmol) in hydrobromic acid (9 ml, 5.7mmol) and water (6 ml), at 0° C., was added aqueous sodium nitritesolution (503 mg, 7.3 mmol) and the mixture was stirred for 15 min. Thismixture was added to copper (I) bromide (899 mg, 6.3 mmol) inhydrobromic acid (9 ml, 5.7 mmol) at 60° C. and the reaction mixture washeated at 95° C. for a further 30 min. After cooling, the mixture waspoured into an ice/water slurry and extracted with ethyl acetate. Thecombined extracts were dried (MgSO₄) and concentrated in vacuo. To theresidue was added ethyl acetate:cyclohexane [1:4] and the solution wasfiltered through silica. The filtrate was concentrated in vacuo to givethe title compound (1.06 g).

Preparation 180 1-(2-Bromo-3,5,6-trimethylphenyl)ethanone

To a mixture of 1-bromo-2,4,5-trimethylbenzene (5.0 g, 25.0 mmol) andacetyl chloride (2.45 ml, 34.5 mmol) in dichloromethane (50 ml) wasadded aluminium chloride (4.42 g, 33.1 mmol) in dichloromethane (50 ml)and the reaction mixture was stirred at room temperature for 18 h. Themixture was poured into water and the two layers were separated. Theorganic phase was washed with saturated aqueous sodium hydrogencarbonate solution, dried (MgSO₄) and filtered through silica. Thefiltrate was concentrated in vacuo to give the title compound (5.50 g).

¹H-NMR (CDCl₃): 2.13-2.17 (3H), 2.22-2.27 (3H), 2.28-2.34 (3H),2.48-2.54 (3H), 6.89-6.92 (1H)

Preparation 1811-Benzyl-2-{1-[2-(difluoromethyl)-3-methylphenyl]vinyl}-1H-imidazole

To a solution of the compound of Preparation 141 (140 mg, 0.36 mmol) in1,4-dioxane:water (9:1, 10 ml) was added trimethylboroxine (50 μl, 0.36mmol) and sodium carbonate (114 mg, 1.08 mmol). The mixture wasdegassed, before addition of[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) chloride (30 mg).The reaction mixture was heated at 100° C. for 18 h, cooled andconcentrated in vacuo. To the residue was added ethyl acetate and thesolution was washed with water, dried (MgSO₄) and filtered throughsilica. The filtrate was concentrated in vacuo to give the titlecompound (110 mg).

Experimental MH⁺ 325.3; expected 325.2

Preparation 182 3-Bromo-2-(difluoromethyl)benzoic acid

To a solution of the compound of Preparation 183 (4.05 g, 11.9 mmol) intetrahydrofuran (120 ml) was added aqueous sodium hydroxide solution(1M, 24.30 ml, 24.3 mmol) and the reaction mixture was stirred at roomtemperature for 18 h. The mixture was partitioned between diethyl etherand water and the two layers were separated. The aqueous layer wasacidified with hydrochloric acid (2M) and extracted with ethyl acetate.The combined extracts were dried (MgSO₄) and concentrated in vacuo togive the title compound (3.06 g).

Experimental MH⁺ 251.1; expected 251.0

Preparation 183 Benzyl 3-bromo-2-(difluoromethyl)benzoate

To a solution of the compound of Preparation 185 (4.1 g, 12.9 mmol) indichloromethane (130 ml) was added (diethylamino)sulphur trifluoride(5.06 ml, 38.6 mmol) and the reaction mixture was stirred at roomtemperature for 18 h. To the mixture was added additionaldichloromethane and saturated aqueous sodium hydrogen carbonate solutionand the two layers were separated. The organic phase was concentrated invacuo and the residue was filtered through silica, eluting withdichloromethane. The filtrate was concentrated in vacuo to give thetitle compound (4.05 g).

¹H-NMR (CDCl₃): 5.23-5.25 (1H), 5.33-5.35 (2H), 7.30-7.41 (4H),7.59-7.64 (2H), 7.85-7.90 (1H)

Similarly prepared was:

Prep. No. Name ¹H-NMR (CDCl₃) From 184 Methyl 3- 3.85-3.88 (3H),6.47-6.76 (1H), Methyl (difluoromethyl)- 7.44-7.50 (1H), 7.61-7.66 (1H),3-formyl- benzoate 8.05-8.13 (2H) benzoate

Preparation 185 Benzyl 3-bromo-2-formylbenzoate

To a solution of the compound of Preparation 186 (4.77 g, 14.9 mmol) inethyl acetate (150 ml) was added manganese (IV) oxide (12.95 g, 148.9mmol) and the reaction mixture was stirred at room temperature for 1 h.The mixture was filtered and the filtrate was concentrated in vacuo togive the title compound (4.11 g).

Experimental MH⁺ 319.1; expected 319.0

Preparation 186 Benzyl 3-bromo-2-(hydroxymethyl)benzoate

A solution of 4-bromo-2-benzofuran-1(3H)-one (4.02 g, 18.9 mmol) inaqueous sodium hydroxide solution (1M, 18.9 ml) was heated at 100° C.for 1 h. The solution was concentrated in vacuo and the residue wasdissolved in toluene and re-concentrated. To a solution of the residuein N,N-dimethylformamide (20 ml) was added benzyl bromide (2.26 ml,18.90 mmol) and the reaction mixture was stirred at room temperature for14 days. The mixture was poured into water and the resulting precipitatewas collected by filtration, washed with water and pentane and dried togive the title compound (4.77 g).

Experimental MH⁺ 321.1; expected 321.0

Preparation 187 3-(Difluoromethyl)benzoic acid

To a solution of the compound of Preparation 184 (188 mg, 1.0 mmol) intetrahydrofuran (5 ml) was added lithium hydroxide monohydrate (85 mg,2.0 mmol). The reaction mixture was stirred at room temperature for 18 hand then acidified by addition of hydrochloric acid (1M). To the mixturewas added water (5 ml) and brine (5 ml) and the solution was extractedwith ethyl acetate (3×10 ml). The combined extracts were dried (MgSO₄)and concentrated in vacuo to give the title compound (290 mg).

¹H-NMR (CDCl₃): 6.50-6.80 (1H), 7.50-7.57 (1H), 7.69-7.74 (1H),8.14-8.21 (2H)

Preparation 188 3-Bromo-5-methylbenzoic acid

To a solution of the compound of Preparation 189 (10.0 g, 43.5 mmol) inacetic acid (45 ml) was added hydrochloric acid (12M, 14.1 ml) and thereaction mixture was heated at 70° C. for 1 h. The solution was cooledto 0° C. and aqueous sodium nitrite solution (5M, 3.0 g, 43.5 mmol) wasadded. After 1 h, the mixture was cooled to −15° C. and aqueoushypophosphorous acid (50%, 23 ml, 170 mmol) was added drop wise. Thereaction mixture was allowed to warm to 10° C. over 2 h and filtered.The solid material was washed with water and cyclohexane and the productwas dried to give the title compound (8.6 g).

¹H-NMR (CDCl₃): 2.32-2.36 (3H), 7.64-7.66 (1H), 7.71-7.74 (1H),7.79-7.82 (1H)

Preparation 189 2-Amino-3-bromo-5-methylbenzoic acid

To a solution of 2-amino-5-methylbenzoic acid (25.0 g, 170 mmol) inacetic acid (250 ml) was added bromine (10 ml, 195 mmol) and thereaction mixture was stirred at room temperature for 2 h. The mixturewas filtered and the solid material was washed with water andcyclohexane and dried to give the title compound (33.4 g).

¹H-NMR (CDCl₃): 2.08-2.13 (3H), 7.42-7.45 (1H), 7.53-7.56 (1H)

Preparation 190 5-Methoxy-2,4-dimethylbenzaldehyde

To a solution of the compound of Preparation 191 (4.12 g, 14 mmol) in1,4-dioxane (30 ml) was added aqueous sodium carbonate solution (15M,2.80 ml, 42 mmol). After purging with nitrogen, trimethylboroxine (1.95ml, 14 mmol) was added, followed by[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.03 g).The reaction mixture was heated at 100° C. for 18 h, cooled and filteredthrough Arbocel®. The filtrate was concentrated in vacuo and to theresidue was added dichloromethane. The solution was filtered throughsilica and the filtrate was concentrated in vacuo to give the titlecompound (988 mg).

¹H-NMR (CDCl₃): 2.19-2.23 (3H), 2.53-2.57 (3H), 3.80-3.85 (3H),7.21-7.24 (2H), 10.23-10.25 (1H)

Preparation 191 2,4-Dibromo-5-methoxybenzaldehyde

To a solution of 3-methoxybenzaldehyde (5.00 g, 4.47 ml, 36.7 mmol) inmethanol (245 ml) was added aqueous sodium bromide solution (5M, 36.7ml, 184 mmol) and aqueous OXONE® solution (45.00 g, 73.4 mmol). Thereaction mixture was stirred at room temperature for 18 h, beforeaddition of aqueous sodium thiosulphate solution (1M, 200 ml) and ethylacetate (400 ml). The two layers were separated and the organic phasewas washed with water and brine, dried (MgSO₄) and concentrated invacuo. The residue was purified by flash chromatography (Biotage)eluting with ethyl acetate:cyclohexane [10:90]. The appropriatefractions were combined and concentrated to give the title compound(4.12 g).

¹H-NMR (CDCl₃): 3.89-3.93 (3H), 7.37-7.39 (1H), 7.79-7.82 (1H),10.20-10.23 (1H)

Preparation 192 1-(2,3-Dimethylphenyl)propan-1-ol

To a solution of 2,3-dimethylbenzaldehyde (1.0 g, 7.5 mmol) in anhydroustetrahydrofuran (50 ml), at −78° C. and under nitrogen, was addedethyllithium (0.5M in benzene:cyclohexane 9:1, 14.9 ml, 7.5 mmol), dropwise via syringe. The reaction mixture was stirred at −78° C. for 30 minand then poured into ice cold hydrochloric acid (2N, 20 ml). The mixturewas extracted with ethyl acetate (2×50 ml) and the combined extractswere dried (MgSO₄) and concentrated in vacuo to give the title compound(1.22 g).

¹H-NMR (CDCl₃): 0.93-0.99 (3H), 1.68-1.76 (2H), 2.18-2.22 (3H),2.25-2.28 (3H), 4.87-4.92 (1H), 7.03-7.13 (2H), 7.28-7.38 (1H)

Preparation 193 1-(3-Chloro-2-hydroxyphenyl)ethanone and1-(3-chloro-4-hydroxyphenyl)ethanone

A solution of 2-chlorophenyl acetate (1.98 g, 11.6 mmol) in1,2-dichlorobenzene (10 ml) was added drop wise to a solution ofaluminium chloride (1.90 g, 13.9 mmol) in 1,2-dichlorobenzene (10 ml).The reaction mixture was heated at 100° C. for 24 h and then cooled,before addition of dichloromethane (10 ml). The mixture was poured intohydrochloric acid (10%, 12 ml), at 0° C., and the two layers wereseparated. The aqueous phase was extracted with dichloromethane and thecombined organic phases were washed with water, dried (MgSO₄) andconcentrated in vacuo. The residue was purified by column chromatography(silica), eluting with cyclohexane. The appropriate fractions werecombined and concentrated to give the title compound as a 1:1 mixture ofregioisomers (1.0 g).

Preparation 194 1-Benzyl-2-[1-(2,3-dimethylphenyl)vinyl]-1H-imidazole

To a suspension of the compound of Preparation 195 (500 mg, 1.63 mmol)in acetonitrile (10 ml) was added thionyl chloride (0.2 mmol, 2.74 mmol)and the reaction mixture was stirred at room temperature for 18 h. Thereaction mixture was concentrated in vacuo and the residue wastriturated with ethyl acetate to give the title compound (450 mg).

Experimental MH⁺ 289.3; expected 289.2

Alternative Synthesis

A solution of the compound of Preparation 195 (82.00 g, 267.6 mmol) inEaton's Reagent (380 ml) was stirred at room temperature for 18 h. Thereaction mixture was poured onto ice and the solution was washed withdiethyl ether and adjusted to pH 7 by addition sodium carbonate. Theaqueous layer was extracted with ethyl acetate and the combined organicextracts were concentrated in vacuo to give the title compound (79.0 g).

Experimental MH⁺ 289.4; expected 289.2

Preparation 1951-(1-Benzyl-1H-imidazol-2-yl)-1-(2,3-dimethylphenyl)ethanol

To a solution of the compound of Preparation 36 (182 g, 626.8 mmol) intetrahydrofuran (1 l), at 0° C., was added methylmagnesium chloride (3Min tetrahydrofuran, 271 ml, 814 mmol). The reaction mixture was stirredat room temperature for 18 h and then poured into hydrochloric acid (2M,500 ml). To the mixture was added diethyl ether (500 ml) and saturatedaqueous sodium chloride solution (100 ml) and the two layers wereseparated. To the aqueous layer was added ethyl acetate (500 ml) andsodium carbonate (50 g) and the organic layer was separated. Theresulting solid material was collected by filtration and triturated withdiethyl ether (300 ml) to give the title compound (82 g).

Experimental MH⁺ 307.4; expected 307.2

Alternative Synthesis

To a solution of methylmagnesium chloride (3M in tetrahydrofuran, 5.0 L,15.2 mol), under nitrogen, was added a solution of the compound ofPreparation 36 (2.8 kg, 9.6 mol) in toluene (6.0 L), at −10° C. Thereaction mixture was stirred at −10° C. for 4 h and then quenched by thedrop wise addition of aqueous ammonium chloride solution (20%, 14.0 L).The resulting solid was collected by filtration and then was slurriedwith water (2×10 L) and filtered. The residue obtained is furtherslurried in acetonitrile (14 L) and filtered. The solid materialcollected by filtration was washed with acetonitrile (2×4 L) and driedin vacuo at 50° C. to give the title compound (2.63 kg, 99.75% pure byHPLC).

Preparation 196 3-[1-(1H-imidazol-2-yl)ethyl]benzamide

A solution of the compound of Preparation 197 (311 mg, 1.35 mmol) inammonium hydroxide (28% in water, 15 ml) was heated at 85° C. for 2 h.The mixture was then cooled and concentrated in vacuo to give the titlecompound (364 mg).

Experimental MH⁺ 216.2; expected 216.1

Preparation 197 Methyl 3-[1-(1H-imidazol-2-yl)ethyl]benzoate

To a solution of the compound of Preparation 198 (477 mg, 1.5 mmol) in2-propanol (10 ml) was added ammonium formate (945 mg, 15.0 mmol) andpalladium (10 wt. % on carbon, 168 mg) and the reaction mixture washeated at 80° C. for 18 h. The mixture was filtered through Arbocel® andthe filtrate was concentrated in vacuo to give the title compound (270mg).

Experimental MH⁺ 231.4; expected 231.1

Preparation 198 Methyl 3-[1-(1-benzyl-1H-imidazol-2-yl)vinyl]benzoate

A mixture of the compound of Preparation 199 (2.55 g, 7.3 mmol) andthionyl chloride (2.12 ml, 29.1 mmol) in acetonitrile (20 ml) wasstirred at room temperature for 18 h. The mixture was concentrated invacuo and the residue was partitioned between ethyl acetate and aqueoussodium hydrogen carbonate solution. The two layers were separated andthe organic phase was filtered through silica and charcoal andconcentrated in vacuo. The residue was purified by column chromatography(silica), with gradient elution, ethyl acetate:cyclohexane [1:1 to 4:1to 1:0]. The appropriate fractions were combined and concentrated togive the title compound (2.32 g).

Experimental MH⁺ 319.3; expected 319.1

Preparation 199 Methyl3-[1-(1-benzyl-1H-imidazol-2-yl)-1-hydroxyethyl]benzoate

To a solution of the compound of Preparation 200 (3.82 g, 11.9 mmol) intetrahydrofuran (25 ml), at 0° C., was added methylmagnesium chloride(3M in tetrahydrofuran, 5.17 ml, 15.5 mmol) and the reaction mixture wasstirred at room temperature for 18 h. The mixture was poured into amixture of ice, hydrochloric acid (2M) and diethyl ether and the twolayers were separated. The aqueous layer was adjusted to pH 7 byaddition of solid sodium hydrogen carbonate and then extracted withethyl acetate. The combined extracts were dried (MgSO₄) and concentratedin vacuo to give the title compound (2.55 g).

Experimental MH⁺ 337.4; expected 337.1

Preparation 200 Methyl 3-[(1-benzyl-1H-imidazol-2-yl)carbonyl]benzoate

A solution of 3-(methoxycarbonyl)benzoic acid (2.53 g, 14.0 mmol) inthionyl chloride (7.17 ml, 98.30 mmol) was heated at reflux for 1 h. Themixture was cooled and concentrated in vacuo and to the residue wasadded toluene. This solution was concentrated in vacuo and to theresidue was added anhydrous acetonitrile (24 ml), 1-benzyl-1H-imidazole(2.22 g, 14.0 mmol) and triethylamine (2.35 ml, 16.9 mmol). The reactionmixture was heated at reflux for 18 h and then cooled and concentratedin vacuo. To the residue was added ethyl acetate and the solution waswashed with water and saturated aqueous sodium hydrogen carbonatesolution. The organic phase was filtered through silica, eluting withethyl acetate, and the filtrate was concentrated in vacuo to give thetitle compound (3.82 g).

Experimental MH⁺ 321.3; expected 321.1

Preparation 201 (2,3-Dimethylphenyl)(1H-imidazol-2-yl)methanol

To a solution of 1-(diethoxymethyl)-1H-imidazole (698 mg, 4.10 mmol) inanhydrous tetrahydrofuran (7 ml), at −78° C., was added n-butyllithium(2.5 M in hexane, 1.64 ml, 4.1 mmol). The reaction mixture was stirredat −78° C. for 1 h, before addition of a solution of2,3-dimethylbenzaldehyde (500 mg, 3.73 mmol) in tetrahydrofuran (3 ml).The reaction mixture was stirred at −78° C. for 2 h, warmed to roomtemperature and quenched with ice cold hydrochloric acid (4M, 20 ml).The reaction mixture was concentrated in vacuo and to the residue wasadded water (20 ml). The solution was extracted with diethyl ether (2×20ml) and the aqueous layer was basified by addition of solid sodiumhydrogen carbonate. This solution was extracted with ethyl acetate (3×20ml) and the combined organic phases were dried (MgSO₄) and concentratedin vacuo to give the title compound (543 mg)

Experimental MH⁺ 203.1; expected 203.1

1. A method of treating a parasite infestation in a mammal comprisingtreating the host animal with an effective amount of a compound offormula (I)

wherein: R¹, R², R³, R⁴, R⁵ are independently selected from the groupconsisting of hydrogen, cyano, nitro, halo, hydroxy, C₁₋₄ alkyloptionally substituted by one or more hydroxy groups, or C₃₋₆ cycloalkylwhich is further optionally substituted by one or more C₁₋₄ alkyl orhalo groups, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl,amino, NR^(x)R^(y), or S(O)_(n)R¹⁰; R⁶ is selected from the groupconsisting of hydrogen, —C₀₋₂alkyleneR⁷, —C₁₋₂alkyleneOR⁷,—C₀₋₂alkyleneC(O)R⁷, —C₁₋₂alkyleneOC(O)R⁷, —C₁₋₂alkyleneOC(O)OR⁷,—C₀₋₂alkyleneC(O)OR⁷, —C₁₋₂alkyleneN(H)C(O)R⁷, —C₁₋₂alkyleneN(R⁷)C(O)R⁷,—C₀₋₂alkyleneC(O)NHR⁷, —C₀₋₂alkyleneC(O)NR¹⁵R¹⁶,—C₁₋₂alkyleneNHC(O)NR¹⁵R¹⁶, —C₁₋₂alkyleneNR⁷C(O)NR¹⁵R¹⁶,—C₁₋₂alkyleneOC(O)NHR⁷, —C₁₋₂alkyleneOC(O)NR¹⁵R¹⁶,—C₀₋₂alkyleneCH═N(R⁷), —C₁₋₂alkyleneP(═O)(NR¹⁵R¹⁶)(NR¹⁵R¹⁶),—C₀₋₂alkyleneSi(R⁷)₃, and —C₀₋₂alkyleneS(O)R¹⁰; where the C₀₋₂alkyleneor C₁₋₂alkylene of R⁶ may, where chemically possible, optionally besubstituted by one or more substituents selected from the groupconsisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₄alkylene(C₃₋₆cycloalkyl),C₀₋₆alkylenephenyl, which C₀₋ ₂alkylene or C₁₋₂alkylene substituent mayin turn be optionally further substituted, where chemically possible, byone or more substituents selected from the group consisting of hydrogen,cyano, nitro, halo, formyl, oxo, hydroxy, C(O)OH, C₁₋₄alkyl,C₁₋₄alkyleneC₃₋₆cycloalkyl, C₁₋₄alkoxy, C₁₋₄alkyleneC₁₋₄alkyoxy,—C(O)OC₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, amino, C₁₋₄alkylamino,C₁₋₄dialkylamino, and S(O)_(n)R¹⁰; where each R⁷, R¹⁵ and R¹⁶, wherechemically possible, is independently selected from the group consistingof hydrogen, C₁₋₈alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₁₋₄alkylene(C₃₋₆cycloalkyl), C₁₋₄alkyleneC₁₋₄alkoxy, C₁₋₆haloalkyl,C₀₋₆alkylenephenyl, C₀₋₆alkylenenaphthyl,C₀₋₆alkylene(tetrahydronaphthyl), and C₀₋₂alkylene(Het), where Het isselected from oxetanyl, tetrahydropyranyl, piperidinyl, morpholinyl,furyl, pyridyl, benzofuranyl, benzothiazolyl, indolyl,2,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, indolyl and1,5-naphthyridinyl; or R¹⁵ and R¹⁶ together with the nitrogen to whichthey are attached may form a three to seven-membered saturated orunsaturated heterocyclic ring optionally containing one or more furtherN, O or S atoms or SO₂ groups; where each of the above R⁷, R¹⁵ or R¹⁶groups may independently include one or more optional substituents wherechemically possible selected from hydrogen, cyano, nitro, halo, formyl,oxo, hydroxy, C(O)OH, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₃₋₆cycloalkyl, C₁₋₄alkyleneC₃₋₆cycloalkyl, C₁₋₄alkoxy,C₁₋₄alkyleneC₁₋₄alkyoxy, C₁₋₄alkoxyC₁₋₄ alkoxy, C₁₋₄alkanoyl,—C(O)OC₁₋₄alkyl, C₁₋₄haloalkyl, C₃₋₆halocycloalkyl, C₁₋₄haloalkoxy,C₁₋₄haloalkanoyl, —C(O)OC₁₋₄haloalkyl, phenyl, 4-halophenyl,4-alkoxyphenyl, 2-cyanophenyl, phenoxy, 4-halophenoxy, benzyloxy,4-halobenzyloxy, benzoyl, pyrazolyl, triazolyl, 2-halo-4-pyrimidinyl,2-phenylethyl, amino, C₁₋₄alkylamino, C₁₋₄ dialkylamino,C(O)N(C₁₋₄alkyl)₂, N(C₁₋₄alkylene)C(O)(C₁₋₄alkyl) and S(O)_(n)R¹⁰; R⁸and R⁹ are independently selected from the group consisting of hydrogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy and C₀₋₄alkylenephenyl but with the proviso that R⁸ and R⁹ are not bothhydrogen; where each of R⁸ and R⁹ may independently include one or moreoptional substituents where chemically possible selected from hydrogen,cyano, halo, hydroxy, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy,—C(O)OC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, and S(O)_(n)R¹⁰; or R⁸and R⁹ together with the carbon to which they are attached may form athree to six membered carbocyclic, saturated ring, which ring isoptionally substituted with one or more substituents selected from thegroup consisting of halo, C₁₋₂ alkyl, C₁₋₂ alkoxy, C₁₋₂ haloalkyl, C₁₋₂haloalkoxy; R¹¹ and R¹² are independently selected from the groupconsisting of hydrogen, halo, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄haloalkyl, and C₁₋₄ haloalkoxy; where R^(x) and R^(y) are independentlyselected from hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and S(O)_(n)R¹⁰;each n is independently 0, 1 or 2; and each R¹⁰ is independentlyhydrogen, hydroxy, C₁₋₄ alkyl, C₁₋₄ haloalkyl, 4-halophenyl, amino, C₁₋₆alkyl amino and di C₁₋₆ alkyl amino; or a pharmaceutically acceptablesalt thereof.
 2. A method of claim 1 wherein in the compound of formula(I) R¹ and R² are methyl; and R³, R⁴, and R⁵ are hydrogen.
 3. A methodof claim 1 wherein in the compound of formula (I) R⁶ is hydrogen,—C₀₋₂alkyleneR⁷, or —C₁₋₂alkyleneOC(O)R⁷.
 4. A method of claim 3 whereinin the compound of formula (I) R⁶ is hydrogen,2,2-dimethylpropionyloxymethyl, propionyloxymethyl,3-cyclopentylpropionyloxy- methyl, 3-methylbutyryloxymethyl,heptanoyloxymethyl, butyryloxymethyl, pentanoyloxymethyl, phenylmethyl,4-methoxybenzyloxycarbonyloxymethyl, cyclopropylmethyl, methyl,cyclopropylmethyloxycarbonyloxymethyl, 3-methylbutoxycarbonyloxymethyl,isopropoxycarbonyloxymethyl, cyclobutoxycarbonyloxymethyl,2,2,2-trifluoroethyloxycarbonyloxymethyl, ethyl, 4-methoxybenzyl,methoxymethyl, 4-(trifluoromethyl)benzyl, isobutoxycarbonyl, orisopropoxycarbonyl.
 5. A method of claim 1 wherein in the compound offormula (I) R⁸ is methyl and R⁹ is hydrogen.
 6. A method of claim 1wherein in the compound of formula (I) R¹¹ and R¹² are hydrogen.
 7. Amethod of claim 1 wherein the compound of formula (I) is selected from acompound of formula (IA) and formula (IB)

wherein R³, R⁴, R⁵, R⁶, R¹¹ and R¹² are hydrogen.
 8. A method of claim 7wherein R¹, R² and R⁶ are methyl; and R⁹ is hydrogen.
 9. A method ofclaim 8 wherein the compound of formula (I) is


10. A method of claim 8 wherein the compound of formula (I) is


11. A method of claim 1 wherein the compound of formula (I) is selectedfrom: 2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;2-[(1R)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;{2-[1-(2,3-dimethylphenyl)ethy]-1H-imidazol1-yl}methylpivalate;{2-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1 -yl}methylpivalate;{2-[(1R)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpivalate;{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol- 1-yl}methylpropionate;{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl3-methylbutanoate;{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylbutyrate;{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl3-cyclopentylpropanoate;{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylheptanoate;{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylpentanoate;2-{1-[2-(trifluoromethyl)phenyl]ethyl}-1H-imidazole;2-[1-(2,5-dimethylphenyl)ethyl]-1H-imidazole;2-[1-(4-chloro-3-methylphenyl)ethyl]-1H-imidazole;2-[1-(3,5-dimethylphenyl)ethyl]-1H-imidazole;1-benzyl-2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl4-methoxybenzylcarbonate;1-(cyclopropymethyl)-2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole;2-1-(2,3-dimethylphenyl)ethyl]-1-methyl-1H-imidazole; cyclopropylmethyl{2-1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylcarbonate;{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl3-methylbutylcarbonate;{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylcarbonate;cyclobutyl{2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methylcarbonate; 2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazol-1-yl}methyl2,2,2-trifluoroethylcarbonate;2-[1-(2,3-dimethylphenyl)ethyl]-1-ethyl-1H-imidazole;2-[1-(2,3-dimethylphenyl)ethyl]-1-(4-methoxybenzyl)-1H-imidazole;2-[1-(2,3-dimethylphenyl)ethyl]-1-(methoxymethyl)- 1H-imidazole;2-[1-(2,3-dimethylphenyl)ethyl]-1-1[4-(trifluoromethyl)benzyl]-1H-imidazole;4-fluorophenyl2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate; isobutyl2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate; isopropyl2-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole-1-carboxylate; an2-[1-(3-methylphenyl)ethyl]-1H-imidazole; or a pharmaceuticallyacceptable salt thereof.
 12. The method of claim 1 wherein the mammal isan animal, a bird or a fish.
 13. The method of claim 12 wherein themammal is an animal.
 14. The method of claim 13 wherein the animal iscats, dogs, horses, cattle, sheep, pigs, goats, equines, or swine. 15.The method of claim 1 wherein the parasite is an insect or acarid. 16.The method of claim 15 wherein the parasite are ticks.
 17. The method oftreating a parasite infestation of claim 1 is a method of controlling aninsect or acarid infestation at a locus.
 18. The method of claim 17comprising applying an effective amount of a compound of formula (I) tosaid locus.
 19. The method of claim 1 wherein the compound of formula(I) is administered orally, parenterally, or topically.